RESUMO
Studies have shown that the consumption of a diet containing whole grains may improve metabolic homeostasis and is related to the reduction of risk factors for the development of obesity, diabetes, cardiovascular diseases, and cancer. We aimed to investigate the effects of Triticum aestivum and Triticum turgidum on the metabolic profile of Wistar rats. Animals were divided into G1 (control group), G2 (T. turgidum), and G3 (T. aestivum). Anthropometric and biochemical parameters were evaluated after 45 days of treatment with both types of wheat. Our results showed that the use of the common or green wheat improved body weight percentage, visceral fat, glycemia, low-density lipoprotein cholesterol, triglycerides, and atherogenic indices such as atherogenic index, CCR1, and CCR2. Furthermore, wheat may also improve high-density lipoprotein cholesterol levels. The health-promoting properties of wheat occur probably due to the content of phytochemicals, antioxidants, and fibers. We suggest that the intake of T. aestivum and T. turgidum may be helpful in the prevention or treatment of obesity, diabetes and cardiovascular diseases.
Assuntos
Metaboloma , Fenômenos Fisiológicos da Nutrição , Triticum , Animais , Antioxidantes , Peso Corporal , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Gordura Intra-Abdominal/metabolismo , Masculino , Compostos Fitoquímicos , Ratos , Ratos Wistar , Receptores CCR1/metabolismo , Receptores CCR2/metabolismo , Fatores de Risco , Triglicerídeos/metabolismoRESUMO
BACKGROUND: Head and neck squamous cell carcinoma shows high prevalence of lymph node metastasis at diagnosis, and despite the advances in treatment, the overall 5-year survival is still under 50%. Chemokine receptors have a role in the development and progression of cancer, but their effect in head and neck carcinoma remains poorly characterised. This study aimed to assess the prognostic value of CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4 in head and neck squamous cell carcinomas. METHODS: Immunohistochemical expression of chemokine receptors was evaluated in a retrospective cohort of 76 cases of head and neck squamous cell carcinoma. Clinicopathological associations were analysed using the chi-square test, survival curves were analysed according to the Kaplan-Meier method, and the Cox proportional hazard model was applied for multivariate survival analysis. RESULTS: The chemokine receptors were highly expressed in primary carcinomas, except for CCR1 and CCR3. Significant associations were detected, including the associations between CCR5 expression and lymph node metastasis (N stage, P = .03), advanced clinical stage (P = .003), poor differentiation of tumours (P = .05) and recurrence (P = .01). The high expression of CCR5 was also associated with shortened disease-free survival (HR: 2.85, 95% CI: 1.09-8.14, P = .05), but the association did not withstand the Cox multivariate survival analysis. At univariate analysis, high expression of CCR7 was associated with disease-free survival and low levels of CXCR4 were significantly associated with both disease-specific and disease-free survival. CONCLUSIONS: These findings show that chemokine receptors may have an important role in head and neck squamous cell carcinoma progression, regional lymph node metastasis and recurrence.
Assuntos
Expressão Gênica , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/patologia , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Idoso , Progressão da Doença , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Receptores CCR1/genética , Receptores CCR1/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Análise de SobrevidaRESUMO
Chronic cardiomyopathy is the main clinical manifestation of Chagas disease (CD), a disease caused by Trypanosoma cruzi infection. A hallmark of chronic chagasic cardiomyopathy (CCC) is a fibrogenic inflammation mainly composed of CD8+ and CD4+ T cells and macrophages. CC-chemokine ligands and receptors have been proposed to drive cell migration toward the heart tissue of CD patients. Single nucleotide polymorphisms (SNPs) in CC-chemokine ligand and receptor genes may determine protein expression. Herein, we evaluated the association of SNPs in the CC-chemokines CCL2 (rs1024611) and CCL5 (rs2107538, rs2280788) and the CCL5/RANTES receptors CCR1 (rs3181077, rs1491961, rs3136672) and CCR5 (rs1799987) with risk and progression toward CCC. We performed a cross-sectional association study of 406 seropositive patients from endemic areas for CD in the State of Pernambuco, Northeast Brazil. The patients were classified as non-cardiopathic (A, n = 110) or cardiopathic (mild, B1, n = 163; severe, C, n = 133). Serum levels of CCL5 and CCL2/MCP-1 were elevated in CD patients but were neither associated with risk/severity of CCC nor with SNP genotypes. After logistic regression analysis with adjustment for the covariates gender and ethnicity, CCL5 -403 (rs2107538) CT heterozygotes (OR = 0.5, P-value = 0.04) and T carriers (OR = 0.5, P-value = 0.01) were associated with protection against CCC. To gain insight into the participation of the CCL5-CCR5/CCR1 axis in CCC, mice were infected with the Colombian T. cruzi strain. Increased CCL5 concentrations were detected in cardiac tissue. In spleen, frequencies of CCR1+ CD8+ T cells and CD14+ macrophages were decreased, while frequencies of CCR5+ cells were increased. Importantly, CCR1+CD14+ macrophages were mainly IL-10+, while CCR5+ cells were mostly TNF+. CCR5-deficient infected mice presented reduced TNF concentrations and injury in heart tissue. Selective blockade of CCR1 (Met-RANTES therapy) in infected Ccr5-/- mice supported a protective role for CCR1 in CCC. Furthermore, parasite antigen stimulation of CD patient blood cells increased the frequency of CCR1+CD8+ T cells and CCL5 production. Collectively, our data support that a genetic variant of CCL5 and CCR1+ cells confer protection against Chagas heart disease, identifying the CCL5-CCR1 axis as a target for immunostimulation.
Assuntos
Cardiomiopatia Chagásica/genética , Quimiocina CCL5/genética , Genótipo , Miocárdio/metabolismo , Trypanosoma cruzi/fisiologia , Adulto , Animais , Brasil , Células Cultivadas , Cardiomiopatia Chagásica/imunologia , Quimiocina CCL2/sangue , Quimiocina CCL2/genética , Quimiocina CCL5/metabolismo , Doença Crônica , Progressão da Doença , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Miocárdio/patologia , Polimorfismo de Nucleotídeo Único , Receptores CCR1/genética , Receptores CCR1/metabolismo , Receptores CCR5/genética , Receptores CCR5/metabolismo , RiscoRESUMO
Allergic asthma is a chronic inflammatory disease characterized by the accumulation of eosinophils, Th2 cells and mononuclear cells in the airways, leading to changes in lung architecture and subsequently reduced respiratory function. We have previously demonstrated that CDIP-2, a chemokine derived peptide, reduced in vitro chemotaxis and decreased cellular infiltration in a murine model of allergic airway inflammation. However, the mechanisms involved in this process have not been identified yet. Now, we found that CDIP-2 reduces chemokine-mediated functions via interactions with CCR1, CCR2 and CCR3. Moreover, using bone marrow-derived eosinophils, we demonstrated that CDIP-2 modifies the calcium fluxes induced by CCL11 and down-modulated CCR3 expression. Finally, CDIP-2 treatment in a murine model of OVA-induced allergic airway inflammation reduced leukocyte recruitment and decreases production of cytokines. These data suggest that chemokine-derived peptides represent new therapeutic tools to generate more effective antiinflammatory drugs.
Assuntos
Anti-Inflamatórios/farmacologia , Peptídeos/farmacologia , Receptores CCR1/metabolismo , Receptores CCR2/metabolismo , Receptores CCR3/metabolismo , Alérgenos , Animais , Anti-Inflamatórios/uso terapêutico , Células CHO , Cálcio/metabolismo , Linhagem Celular Tumoral , Quimiotaxia/efeitos dos fármacos , Cricetulus , Citocinas/metabolismo , Eosinófilos/efeitos dos fármacos , Eosinófilos/fisiologia , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Linfonodos/citologia , Camundongos Endogâmicos BALB C , Ovalbumina , Peptídeos/uso terapêutico , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Receptores CCR1/genética , Receptores CCR2/genética , Receptores CCR3/genética , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/patologiaRESUMO
Any of the four dengue serotypes can cause a severe disease, partly due to systemic inflammation orchestrated by mediators like cytokines and chemokines. We addressed the role of CCR1 and its ligands CCL3/MIP-1α and CCL5/RANTES in dengue infection using three different approaches: an ex vivo model exploring memory immune response in subjects with a well characterized dengue immune background, an in vivo study in patients with primary or secondary dengue infection, and an approach in fatal dengue. CCR1 and CCL3/MIP-1α gene expression showed differences after homotypic and heterotypic challenge according to dengue immune background of subjects, in correspondence with previous observations in Cuban dengue outbreaks. CCL5/RANTES gene expression was higher after homotypic challenge. CCR1 and CCL3/MIP-1α gene expression was higher in patients with secondary infection during critical days of the dengue disease, while the increase in RANTES expression started earlier than the observed for CCR1 and CCL3/MIP-1α. CCR1 and CCL3/MIP-1α gene expression was as high in brain as in spleen tissue from necropsy. Our results confirm the strong influence of previous immunity in subsequent dengue infections, and confer a possible pathogenic role to CCR1 and CCL3/MIP-1α in dengue disease and a possible protective role for CCL5/RANTES, probably through CCR5 interaction.
Assuntos
Quimiocina CCL3/metabolismo , Quimiocina CCL5/metabolismo , Dengue/metabolismo , Receptores CCR1/metabolismo , Adulto , Encéfalo/metabolismo , Encéfalo/virologia , Quimiocina CCL3/genética , Quimiocina CCL5/genética , Cuba , Dengue/genética , Dengue/imunologia , Vírus da Dengue/imunologia , Feminino , Expressão Gênica , Regulação da Expressão Gênica , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Ligantes , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Receptores CCR1/genética , Baço/imunologia , Baço/metabolismo , Baço/virologia , Adulto JovemRESUMO
The testis is considered an immunologically privileged site where germ cell antigens are protected from autoimmune attack. Yet in response to infections, inflammatory diseases, or trauma, there is an influx of leukocytes to testicular interstitium. Interactions between endothelial cells (EC) and circulating leukocytes are implicated in the initiation and evolution of inflammatory processes. Chemokines are a family of chemoattractant cytokines characterized by their ability to both recruit and activate cells. Thus, we investigated the expression of CCL3, its receptors, and adhesion molecules CD31 and CD106 in an in vivo model of experimental autoimmune orchitis (EAO). In EAO, the highest content of CCL3 in testicular fluid coincides with onset of the disease. However, CCL3 released in vitro by testicular macrophages is higher during the immunization period. The specific chemokine receptors, CCR1 and CCR5, were expressed by testicular monocytes/macrophages and an increased number of CCR5+ cells was associated with the degree of testicular lesion. EC also play an essential role by facilitating leukocyte recruitment via their ability to express cell surface adhesion molecules that mediate interactions with leukocytes in the bloodstream. Rats with EAO showed a significant increase in the percentage of CD31+ EC that upregulate the expression of CD106. The percentage of leukocytes isolated from peripheral blood and lymph nodes expressing CD49d (CD106 ligand) also increases during orchitis. These data suggest that cell adhesion molecules, in conjunction with chemokines, contribute to the formation of a chemotactic gradient within the testis, causing the leukocyte infiltration characteristic of EAO histopathology.
Assuntos
Doenças Autoimunes/imunologia , Autoimunidade , Moléculas de Adesão Celular/metabolismo , Quimiocinas/metabolismo , Quimiotaxia de Leucócito , Orquite/imunologia , Receptores de Quimiocinas/metabolismo , Testículo/imunologia , Animais , Doenças Autoimunes/patologia , Células Cultivadas , Quimiocina CCL3/metabolismo , Modelos Animais de Doenças , Células Endoteliais/imunologia , Macrófagos/imunologia , Masculino , Orquite/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores CCR1/metabolismo , Receptores CCR5/metabolismo , Testículo/patologia , Fatores de Tempo , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in many tropical countries. Recent clinical data have shown an association between levels of different chemokines in plasma and severity of dengue. We evaluated the role of CC chemokine receptors CCR1, CCR2 and CCR4 in an experimental model of DENV-2 infection in mice. Infection of mice induced evident clinical disease and tissue damage, including thrombocytopenia, hemoconcentration, lymphopenia, increased levels of transaminases and pro-inflammatory cytokines, and lethality in WT mice. Importantly, infected WT mice presented increased levels of chemokines CCL2/JE, CCL3/MIP-1α and CCL5/RANTES in spleen and liver. CCR1â»/â» mice had a mild phenotype with disease presentation and lethality similar to those of WT mice. In CCR2â»/â» mice, lethality, liver damage, levels of IL-6 and IFN-γ, and leukocyte activation were attenuated. However, thrombocytopenia, hemoconcentration and systemic TNF-α levels were similar to infected WT mice. Infection enhanced levels of CCL17/TARC, a CCR4 ligand. In CCR4â»/â» mice, lethality, tissue injury and systemic inflammation were markedly decreased. Despite differences in disease presentation in CCR-deficient mice, there was no significant difference in viral load. In conclusion, activation of chemokine receptors has discrete roles in the pathogenesis of dengue infection. These studies suggest that the chemokine storm that follows severe primary dengue infection associates mostly to development of disease rather than protection.
Assuntos
Vírus da Dengue/metabolismo , Dengue/metabolismo , Receptores CCR1/metabolismo , Receptores CCR2/metabolismo , Receptores CCR4/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Interferon gama/metabolismo , Interleucina-6/metabolismo , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peroxidase/metabolismoRESUMO
BACKGROUND: Successful implantation is followed by a local pro-inflammatory and Th1 response, subsequently controlled by Th2. Regulated upon activation, normal T cell expressed and secreted (RANTES) promotes a Th1 response and is implicated as a physiologic tolerogenic factor; therefore, we studied its potential role in the trophoblast-maternal leukocyte dialog. METHODS: We performed co-cultures of immortalized trophoblast cell line (Swan 71) and peripheral blood mononuclear cells (PBMCs) from fertile women (n = 23) or with recurrent spontaneous abortions (n = 18, RSA). After 24 and 48 h, supernatant and cells were analyzed by enzyme-linked immunosorbent assay, fluorescence-activated cell sorting, Western blot and apoptosis assay. To investigate the physiological effects at peripheral level, we co-cultured maternal and paternal PBMCs with conditioned media from Swan cells and progesterone. RESULTS: Following interaction of maternal PBMCs and trophoblast cells, RANTES production increased (P < 0.05) and was accompanied by low levels of interferon gamma, interleukin-12 p70 and high levels of tumor necrosis factor-alpha, nitrites and leukemia-inhibitory factor. RANTES production resulted in elevated apoptosis of potentially deleterious maternal CD3+ lymphocytes, accompanied by a decrease in the proliferative maternal response. During fetal-maternal dialog, the anti-RANTES antibody significantly reduced the frequency of CD4+CD25+Foxp3+ cells (P < 0.05) and was associated with trophoblast cell survival. However, co-cultures of Swan cells and RSA-PBMCs displayed a differential RANTES kinetics, lower levels of regulatory T cells (Tregs) and CD3+annexin-V+cells, accompanied by higher levels of apoptotic trophoblast cells. CONCLUSIONS: RANTES promotes an adequate pro-implantatory microenvironment that influences trophoblast cell survival and modulates the balance of maternal Treg/T effector lymphocytes in favor of maternal tolerance.
Assuntos
Apoptose/imunologia , Quimiocina CCL5/fisiologia , Leucócitos Mononucleares/imunologia , Linfócitos T/imunologia , Trofoblastos/imunologia , Aborto Habitual/imunologia , Western Blotting , Linhagem Celular , Proliferação de Células , Quimiocina CCL5/metabolismo , Meios de Cultivo Condicionados , Implantação do Embrião/imunologia , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Leucócitos Mononucleares/fisiologia , Troca Materno-Fetal/imunologia , Gravidez , Receptores CCR1/metabolismo , Receptores CCR5/metabolismo , Linfócitos T/citologia , Linfócitos T/fisiologia , Trofoblastos/metabolismo , Trofoblastos/fisiologiaRESUMO
Chemokines are small chemotactic cytokines that can induce the migration of leukocytes, activate inflammatory/immune responses and have recently been implicated in the regulation of tumor growth and organ-specific spread. In this setting, the macrophage inflammatory protein-1alpha (CCL3) chemokine displays a diversity of roles that may contribute to the directional migration of squamous cells into cervical lymph nodes or to the defense against tumor initiation and progression. Thus, the aim of this study was to determine, for the first time, the expression of CCL3 and their receptors, CCR1 and CCR5, by real-time polymerase chain reaction in samples obtained from oral squamous cell carcinoma (OSCC) and healthy gingival tissue (control). In addition, we investigated the immunoexpression of these molecules in neoplastic cells (parenchyma), inflammatory/immune cells (stroma) in primary OSCC and in metastatic and non-metastatic lymph node tissues. The relationship of CCL3/CCR1 with survival data was also evaluated. The analysis of mRNA expression revealed a significantly higher expression of CCL3 and CCR1 in OSCC compared with the controls (P<0.05). The expression of CCR5 was not different in the two groups. The percentages of CCL3+ and CCR1+ cells were observed to be similar in parenchyma and stroma in the OSCC without lymph node metastasis when compared with OSCC with lymph node metastasis (P>0.05). However, we observed the density of CCL3+ nodal cells to be significantly higher in metastatic lymph nodes when compared with non-metastatic lymph nodes in the same patients (P<0.05). Considering CCL3 in stroma, the mean survival rate for patients with high CCL3+ cell percentage was better than for those with low CCL3+ cell percentage. Our findings suggest that the CCL3/CCR1 axis may have a role in the spread of tumoral cells to the lymph nodes and also in the local host defense against the tumor.