RESUMEN
BACKGROUND: Obesity is a serious health problem that dysregulate Renin-Angiotensin System (RAS) and intestinal microbiota. OBJECTIVE: The present study aimed to evaluate the Angiotensin-(1-7) [ANG-(1-7)] oral formulation effects on obese mice intestinal microbiota. METHODS: Mice were divided into four groups: obese and non-obese treated with ANG-(1-7) and obese and non-obese without ANG-(1-7) during four weeks. RESULTS: We observed a significant decrease in the fasting plasma glucose, total cholesterol, triglycerides, and Low-density lipoprotein levels and increased High-density lipoprotein in animals treated with ANG-(1-7). The histological analysis showed intestinal villi height reduction in mice treated with ANG-(1-7). Additionally, increased Bacteroidetes and decreased Firmicutes (increased Bacteroidetes/ Firmicutes ratio) and Enterobacter cloacae populations were observed in the High-Fat Diet + ANG-(1-7) group. Receptor toll-like 4 (TLR4) intestinal mRNA expression was reduced in the HFD+ANG-(1-7) group. Finally, the intestinal expression of the neutral amino acid transporter (B0AT1) was increased in animals treated with ANG-(1-7), indicating a possible mechanism associated with tryptophan uptake. CONCLUSION: The results of the present study suggest for the first time an interaction between oral ANG-(1-7) and intestinal microbiota modulation.
Asunto(s)
Angiotensina I/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Metaboloma/efectos de los fármacos , Obesidad/tratamiento farmacológico , Fragmentos de Péptidos/farmacología , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Glucemia/metabolismo , Colesterol/metabolismo , Biología Computacional , Dieta Alta en Grasa , Humanos , Intestinos/efectos de los fármacos , Lipoproteínas LDL/metabolismo , Masculino , Ratones , Ratones Obesos , Receptor Toll-Like 4/metabolismo , Triglicéridos/metabolismoRESUMEN
BACKGROUND: Obesity and non-alcoholic fatty liver disease (NAFLD) have been increasing at an alarming rate worldwide. Bifidobacterium longum (BL), a common member of the human gut microbiota, has important health benefits through several mechanisms. OBJECTIVES: We evaluated the BL supplementation effects on body metabolism and renin-angiotensin components hepatic expression in mice fed a high-fat diet. METHODS: Thirty-two male mice were divided into four groups: standard diet + placebo (ST), standard diet + Bifidobacterium longum (ST + BL), high-fat diet + placebo (HFD) and high-fat diet + Bifidobacterium longum (HFD + BL). Following the obesity induction period, the ST + BL and HFD + BL groups were supplemented with Bifidobacterium longum for 4 weeks. Then, body, biochemical, histological and molecular parameters were evaluated. RESULTS: HFD + BL mice had a significant decrease in adipose tissue mass and blood glucose levels, as well as a significant reduction in blood glucose during an intraperitoneal glucose tolerance test. The treatment also resulted in reduced levels of total cholesterol and hepatic fat accumulation. Moreover, we observed an increase in angiotensin converting enzyme 2 (ACE2) and Mas receptor (MASR) expression levels in BL-treated obese mice. CONCLUSIONS: These data demonstrate that BL may have the potential to prevent obesity and NAFLD by modulating the mRNA expression of renin-angiotensin system components.
Asunto(s)
Bifidobacterium longum/fisiología , Suplementos Dietéticos , Hígado/efectos de los fármacos , Obesidad/metabolismo , Probióticos/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Animales , Glucemia/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Obesidad/prevención & control , Probióticos/administración & dosificación , Proto-Oncogenes MasRESUMEN
Ethnicity is an important determinant of blood pressure levels, being black individuals affected more than any other ethnic group. Arterial stiffening, an independent risk factor for hypertension, is also influenced by ethnicity. However, whether black individuals from different continents would have different patterns of arterial stiffening is still unknown. Thus, the authors aimed to compare pulse wave velocity (PWV) in black subjects living in Angola and Brazil. A total of 677 black individuals from two independent cross-sectional studies conducted in Brazil and Angola were included in this analysis. Carotid-to-femoral PWV was measured following the same protocols for both studies, as well as clinical and anthropometric variables. Adjusted PWV was higher in Brazilian blacks than in Angolans, regardless of sex (men from Brazil: 10.7 ± 1.8 vs men from Angola: 9.9 ± 1.8 m/s, P < .001; women from Brazil: 10.3 ± 1.5 vs women from Angola: 9.2 ± 1.3 m/s, P < .001). Although the cf-PWV was higher in Brazilian blacks, the age-related increase in cf-PWV was higher in Angolan men compared to Brazilians, but not in women. SBP showed the strongest association with cf-PWV, regardless of sex and country. However, age was associated with cf-PWV in all groups, except in Brazilian men. Our results clearly show a difference in PWV between two black populations, and highlight for sex differences in the hemodynamic parameters that might affect blood pressure levels in these populations.
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Hipertensión , Rigidez Vascular , Adulto , Negro o Afroamericano , Angola/epidemiología , Presión Sanguínea , Brasil/epidemiología , Estudios Transversales , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/epidemiología , Masculino , Análisis de la Onda del PulsoRESUMEN
Hypertension is responsible for high morbidity and mortality as one of the most important cardiometabolic risk factors. The aim of the study was to investigate whether the Gln223Arg in the leptin receptor (LEPR) influences the prevalence of hypertension. A cross-sectional study was carried out in individuals aged ≥ 18 years. Polymorphism identification was performed using PCR-RFLP analysis. Participants with blood pressure ≥ 140/90 mmHg or medication use were considered hypertensive. Frequencies, means, cross-tabulations, and multivariate models were produced to study differences in hypertension prevalence by genotypes. The study includes 470 participants. The frequency of GG polymorphism variant was 10.43%, 46.81% AG, and 42.77% AA. The distribution of hypertension frequency by LEPR genotypes was the following: AA 43.8%, AG 40.4%, and GG 40.8%; there were no significant differences between groups. Comparative analysis which used multivariate Poisson regression adjusted by many potential confounders (age, sex, schooling, smoking, alcohol intake, obesity, and family history of parental obesity) did not modify this result. In this large sample of population-based study, the association of the LEPR Gln223Arg gene polymorphism with hypertension was not observed.
RESUMEN
BACKGROUND: Increased expression of microRNAs (miRNAs), miR-21, miR-345, and miR-181b has been demonstrated in oral leukoplakia (OL) that progresses to oral squamous cell carcinoma (OSCC), suggesting a miRNA signature with potential prognostic value. On the basis of these findings, this pilot study aimed to investigate the cytological and histopathological features that are used to grade oral dysplasia and determine associations with the expression of these 3 potentially cancer-related miRNAs. We also compared the expression levels of these miRNAs in OL with normal oral mucosa and OSCC. METHODS: We evaluated miRNA expression by qPCR in 22 samples of OL demonstrating different grades of dysplasia, as well as 17 cases of OSCC, and 6 samples of normal oral mucosa. We associated the miRNAs expression profiles with cytological and histopathological features of OL. RESULTS: OSCC cases showed increased expression of all 3 miRNAs when compared with OL and normal oral mucosa. Increased expression of miR-21 was also observed in OL when compared with normal oral mucosa. We found a higher expression of miR-21 and miR-181b in OL that presented with an increased number of mitotic figures, increased nuclear/cytoplasmic ratio, or hyperchromasia. Increased expression of miR-21 was also detected in OL with abnormally superficial mitosis. Higher expression of miR-345 was observed in OL with an increased number and size of nucleoli or increased nuclear/cytoplasmic ratio. CONCLUSIONS: In conclusion, the present study shows that some cytological and histopathological parameters used to grade dysplasia are associated with altered miRNA expression.
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Leucoplasia Bucal/química , MicroARNs/análisis , Adulto , Anciano , Anciano de 80 o más Años , Nucléolo Celular/ultraestructura , Núcleo Celular/ultraestructura , Citoplasma/ultraestructura , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucoplasia Bucal/patología , Masculino , Persona de Mediana Edad , Mitosis , Mucosa Bucal/química , Neoplasias de la Boca/química , Neoplasias de la Boca/patología , Proyectos Piloto , Lesiones Precancerosas/química , Lesiones Precancerosas/patologíaRESUMEN
The expression of metalloproteinases and their inhibitors has been related to different invasive and metastatic potentials in cancer. This study aims to investigate the immunohistochemical expression of TIMP-3 and MMP-9 in samples of basal cell carcinoma (BCC), squamous cell carcinoma of the skin (SCC), and actinic keratosis (AK). Immunohistochemistry was performed to evaluate the expression of TIMP-3 and MMP-9 in samples of BCC (n=22), SCC (n=10), and AK (n=15). Ten fields of both tumor parenchyma and tumor stroma were photographed and counted in image software. The ratio of positive cells to total cells was used to quantify the staining. A higher expression of MMP-9 was found in tumor stroma of SCC compared to BCC and AK. No significant differences in TIMP-3 expression were observed among the groups. Considering the well-described differences between these neoplasms, these results provide additional evidence of the role of MMP-9 in tumor invasiveness of keratinocyte-derived tumors.
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Biomarcadores de Tumor/análisis , Carcinoma Basocelular/enzimología , Carcinoma de Células Escamosas/enzimología , Inmunohistoquímica , Queratosis Actínica/enzimología , Metaloproteinasa 9 de la Matriz/análisis , Neoplasias Cutáneas/enzimología , Inhibidor Tisular de Metaloproteinasa-3/análisis , Adulto , Anciano , Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Queratosis Actínica/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Cutáneas/patologíaRESUMEN
Cancer cells need to develop microvessels in order to grow and to establish metastatic foci. A role for the p53 protein in the regulation of the angiogenic process is suggested. This study aimed to investigate the relationship between immunohistochemical expression of microvessel density (MVD), measured by CD31 staining, and p53 protein with clinicopathologic factors, and survival in head and neck squamous cell carcinoma (n=70). Tumor angiogenesis was estimated by determining MVD in areas with the highest number of stained microvessels (hot spots). Clinicopathologic factors and immunohistochemical data were evaluated by χ statistical test and were submitted to binary logistic regression to analyze the risk of presence of lymph node metastasis. Factors that might predict survival were investigated using Cox proportional hazards tests. Differences were considered statistically significant when P<0.05. The percentage of p53-positive cells showed no association with clinicopathologic parameters and MVD. Patients with locoregional metastasis presented statistically significant higher MVD (P=0.043). Individuals presenting head and neck squamous cell carcinoma in posterior sites (P=0.022; OR=3.644) and higher MVD (P=0.039; OR=3.247) had a significant increase in risk of metastasis occurrence. Multivariate analysis showed that presence of lymph node metastasis was statistically significant for overall survival of head and neck carcinoma patients (P=0.006; OR =2.917). The present data suggest that MVD represents a promising diagnostic tool to identify individuals with increased risk for the development of metastatic disease, which is very indicative of poor prognosis.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Neoplasias de Cabeza y Cuello/diagnóstico , Microvasos/patología , Proteína p53 Supresora de Tumor/metabolismo , Anciano , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neovascularización Patológica , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Valor Predictivo de las Pruebas , Pronóstico , Riesgo , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/genéticaRESUMEN
AIMS: This study has compared the tissue expression of the p53 tumour suppressor protein and DNA repair proteins APE1, hMSH2 and ERCC1 in normal, dysplastic and malignant lip epithelium. METHODS AND RESULTS: Morphological analysis and immunohistochemistry were performed on archived specimens of normal lip mucosa (n=15), actinic cheilitis (AC) (n=30), and lip squamous cell carcinoma (LSCC) (n=27). AC samples were classified morphologically according to the severity of epithelial dysplasia and risk of malignant transformation. LSCC samples were morphologically staged according to WHO and invasive front grading (IFG) criteria. Differences between groups and morphological stages were determined by bivariate statistical analysis. Progressive increases in the percentage of epithelial cells expressing p53 and APE1 were associated with increases in morphological malignancy from normal lip mucosa to LSCC. There was also a significant reduction in epithelial cells expressing hMSH2 and ERCC1 proteins in the AC and LSCC groups. A higher percentage of malignant cells expressing APE1 was found in samples with an aggressive morphological IFG grade. CONCLUSIONS: Our data showed that epithelial cells from premalignant to malignant lip disease exhibited changes in the expression of p53, APE1, hMSH2 and ERCC1 proteins; these molecular change might contribute to lip carcinogenesis.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Proteínas de Unión al ADN/metabolismo , Endonucleasas/metabolismo , Neoplasias de los Labios/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Carcinoma de Células Escamosas/patología , Diferenciación Celular , Queilitis/metabolismo , Queilitis/patología , Femenino , Humanos , Inmunohistoquímica , Neoplasias de los Labios/patología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
AIMS: To determine the contributions of mast cells (MC), eosinophil leucocytes (EL) and microvessel density (MVD) in lip carcinogenesis, and to establish the relationships between these biomarkers and their possible prognostic value in lip squamous cell carcinoma (LSCC). METHODS AND RESULTS: Archived specimens of lip mucosa (n=13), actinic cheilitis (n=29) and LSCC (n=29) were formalin-fixed, paraffin-embedded, sectioned and stained with toluidine blue and haematoxylin and eosin (H&E) in order to identify MC and EL and to measure their densities. Tumour angiogenesis was estimated by determining, with the use of CD31 antibody MVD in areas with the highest number of stained microvessels ('hot spots'). Progressive increases of MC, EL and MVD were observed during lip tumour development. Correlation analysis revealed positive associations between the biomarkers during tumour progression. In LSCC samples, significant associations were found between MVD values and metastatic disease. On multivariate analysis, MVD was a predictor of risk of cervical metastasis. CONCLUSIONS: The densities of MC, EL and microvessels increase during lip carcinogenesis, and for MC and EL this may be related to the stimulation of tumour angiogenesis. MVD could be a useful predictor of cervical metastasis in LSCC.
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Carcinoma de Células Escamosas/patología , Eosinófilos/patología , Neoplasias de los Labios/patología , Mastocitos/patología , Neovascularización Patológica/patología , Adulto , Anciano , Queilitis/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Microvasos , Persona de Mediana Edad , Mucosa Bucal/patologíaRESUMEN
BACKGROUND: Genetic factors are known to be involved in oral squamous cell carcinoma (OSCC) development. METHOD: We evaluated a possible association between CCND1 A870G and P21/WAF1 C98A polymorphisms and OSCC, as well as the impact of the genotypes on protein immunoexpression. The study group consisted of 80 individuals with histopathological diagnosis of OSCC and the control group consisted of 80 healthy individuals without oral lesions and matched by age, sex and tobacco usage. The genotypes were studied by the polymerase chain reaction and restriction fragment length polymorphic analysis. Paraffin-embedded sections were used for immunohistochemical analysis. RESULTS: No statistical association between CCND1 and/or P21/WAF1 genotypes and OSCC was demonstrated, although we found that people harbouring the combined presence of at least one variant allele of both genes showed a 1.8 times more chance of developing OSCC compared to the referent genotype. OSCC tumours from individuals with P21 heterozygous genotype showed a significantly higher immunopositivity than tumours from wild-type individuals. CONCLUSION: The present study did not demonstrate a significant association between CCND1 and / or P21 / WAF1 genotypes and OSCC. However, P21 protein expression in OSCC tumours is affected by P21 / WAF1 genotype.
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Carcinoma de Células Escamosas/genética , Ciclina D1/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Neoplasias de la Boca/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Carcinoma de Células Escamosas/química , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Expresión Génica , Frecuencia de los Genes , Humanos , Inmunohistoquímica , Modelos Logísticos , Persona de Mediana Edad , Neoplasias de la Boca/química , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
In the present study, the neuroprotective effect of blockers of voltage-dependent calcium channels (VDCC) and intracellular calcium stores on retinal ischemic damage induced by oxygen deprivation-low glucose insult (ODLG) was investigated. Retinal damage induced by ODLG was dependent on the calcium concentration in the perfusion medium. When incubated in medium containing 2.4 mM CaCl(2), cell death in ischemic retinal slices treated with blockers of VDCC, omega-conotoxin GVIA (1.0 microM), omega-conotoxin MVIIC (100 nM) and nifedipine (1.0 microM), was reduced to 62 +/- 2.3, 46 +/- 4.3 and 47 +/- 3.9%, respectively. In the presence of blockers of intracellular calcium stores, dantrolene (100 microM) and 2-APB (100 microM), the cell death was reduced to 46 +/- 3.2 and 55 +/- 2.9%, respectively. Tetrodotoxin (1.0 microM), reducing the extent of the membrane depolarization reduces the magnitude of calcium influx trough VDCC causing a reduction of the cell death to 55 +/- 4.3. Lactate dehydrogenase content of untreated ischemic retinal slices was reduced by 37% and treatment of ischemic slices with BAPTA-AM (100 microM) or 2-APB (100 microM) abolished the leakage of LDH. Dantrolene (100 microM) and nifedipine (1.0 microM) partially blocked the induced reduction on the LDH content of retinal ischemic slices. Histological analysis of retinal ischemic slices showed 40% reduction of ganglion cells that was prevented by BAPTA-AM or dantrolene. 2-APB partially blocked this reduction whilst nifedipine had no effect, p > 0.95. Conclusion Blockers of VDCC and intracellular calcium-sensitive receptors exert neuroprotective effect on retinal ischemia.