The principal substrate used by the normal adult human heart is free fatty acids, the remainder being, predominantly,carbohydrate. During failure, the heart becomes less reliant on fatty acid metabolism, possibly as a result of tissue hypoxia. Therefore, understanding hypoxic adaptation may explain the metabolic changes that occur during the development of heart failure.As peroxisome proliferator activated receptor alpha (PPARα) modulates cardiac fatty acid metabolism, the work in this thesis focused on the role of PPARα in cardiac metabolic adaptation to chronic hypoxia. It was found that isolated hearts from chronically hypoxic (11% O₂ for 3 weeks)mice were more glycolytic, had reduced PPARα expression and decreased fatty acid metabolism,but had normal function, determined using in vivocine-MRI. ³¹P MRS of isolated perfused mouse hearts showed a drop in PCr with hypoxia, but ΔG_ATP was not altered, indicating that metabolic reprogramming was sufficient to maintain ATP production and contractile function. Increased or decreasedPPARα expression, using a high fat diet or PPARα null mice, respectively, prevented metabolic adaptation to hypoxia and caused cardiac dysfunction. Hypoxia with high fat feeding was particularly deleterious, reducing ejection fraction by 9%,possibly due to increased mitochondrial uncoupling. PPARβ/δ and γ were not involved in the adaptation to hypoxia, and none were modified by PPARα stimulation or ablation. Cardiac VEGF and PDK1, prominent hypoxia-inducible factor (HIF) targets, were increased by hypoxia, indicating that HIF may have been involved in metabolic adaption. However, high fat feeding prevented VEGF accumulation during hypoxia, suggesting that impaired HIF signalling may have contributed to the maladaptive response to hypoxia. In order to determine the relationship between HIF and PPARα, HIFwas stabilised pharmacologically using FG2216/BIC in HL-1 cardiomyocytes, to show decreased PPARα expression and caused similar metabolic changes to those seen in the in vivo hypoxic heart. In conclusion, this study demonstrated that HIF downregulation of PPARα is crucial for metabolic adaptation and maintenance of cardiac function during chronic hypoxia. Similar metabolic changes that occur in end-stage heart failure may also be a response to increasing hypoxia.

Introduction: An increased gluteofemoral adipose tissue (AT) mass is associated with a protective cardiovascular and metabolic risk profile, and effective fatty acid retention in femoral AT has been proposed as a possible mechanism. Catecholamines are important regulators of AT lipolysis and blood flow (ATBF). The aim of the thesis was to investigate regional differences in the adrenergic regulation of fatty acid release and ATBF between abdominal and femoral AT in vivo. Furthermore, in vivo regional fatty acid trafficking was studied in a physiological setting over 24 h. Methods: Regional fatty acid trafficking, along with the measurement of ATBF, was studied with the arterio-venous difference technique and stable isotope tracers in healthy volunteers. Adrenergic agonists (isoprenaline, adrenaline) were infused either locally by microinfusion, or systemically. Local microinfusion of adrenoreceptor antagonists (propranolol, phentolamine) was used to characterize specific adrenoreceptor subtype effects. The trafficking of dietary fatty acids was studied over a 24 h period involving three meals containing stable isotope-labelled fatty acids along with intravenous infusions of another labelled fatty acid. Results: Femoral ATBF and lipolysis was less responsive to adrenergic stimulation with adrenaline compared to abdominal AT. This was due to increased femoral α-adrenoreceptor responsiveness. When studied over 24 h, femoral AT showed a lower lipolysis rate compared to abdominal AT, while dietary fatty acids were extracted more avidly by abdominal AT. Uptake of non-dietary fatty acids (derived from very-low-density lipoproteins or unbound non-esterified fatty acids) was comparable between abdominal and femoral AT. Conclusion: There are fundamental differences in response to adrenergic stimuli between abdominal and gluteofemoral tissues and the ability of femoral AT to trap non-dietary fatty acids may provide protection of other tissues from ectopic fatty acid deposition.

Regular aerobic exercise has a wide range of positive effects on health and cognition. Exercise has been demonstrated to provide a particularly powerful and replicable method of triggering a wide range of structural changes within both human and animal brains. However, the details and mechanisms of these changes remain poorly understood. This thesis undertakes a comprehensive examination of the relationship between brain plasticity and aerobic exercise. A large, longitudinal experiment was conducted in which healthy but sedentary participants were scanned before and after six-weeks of monitored aerobic exercise. Increases in the volume of the anterior hippocampus were observed, as previously reported in an older cohort after a longer exercise intervention. Multimodal imaging methods allowed an in-depth exploration of the mechanisms underlying this volume change, which proved to be dominated by white matter changes rather than the vascular changes that have been previously reported. A surprising global change in the balance of CSF, blood, and brain tissue within the cranial cavity was also observed. Cross-sectional differences in memory and brain structure associated with fitness were also observed. The volume of the anterior hippocampus was shown to correlate with a measure of working memory. Higher cerebral blood volume throughout the brain was found to correlate with greater fitness and better working memory. Focal associations between fitness and magnetic susceptibility, a measure of iron content, were also observed in the basal ganglia. These findings demonstrate that aerobic fitness is associated with improved cognition and brain structure throughout the lifespan rather than simply acting to mitigate age related brain atrophy or accelerate brain development. Finally, a new pipeline was developed for analysing hippocampal morphometry using high-resolution, 7 Tesla scans. Striking variability in the convolution of the hippocampal surface is reported. This technique shows promise for imaging the precise nature of the change in hippocampal volume associated with aerobic exercise. This thesis adds to the evidence that aerobic exercise is a potent catalyst for behavioural and brain plasticity while also demonstrating that the mechanisms for those plastic changes are likely different than previously supposed. Future work will refine these measurement techniques, perhaps to a point where brain changes can be monitored on a single subject level. This work will provide an important tool to understand how best to utilize aerobic exercise to facilitate adaptive behavioural changes, mitigate the negative effects of ageing and disease on the brain, and maximize the benefits of active lifestyles.

Introdução: O Phyllanthus niruri (P. niruri) ou quebra pedra é uma planta com ação antilitogênica. No entanto, estudos clínicos nesta área ainda são escassos na literatura. O objetivo principal deste estudo foi avaliar prospectivamente os efeitos do P. niruri nos parâmetros metabólicos de pacientes com litíase urinária e, secundariamente, avaliar o impacto da ingestão do chá da planta na eliminação de cálculos urinários. Material e Métodos: Foram estudados 56 pacientes portadores de cálculos renais <10 mm. Avaliação clínica, metabólica e ultrassonográfica do trato urinário foram realizadas antes do uso do P. niruri (infusão de 500 ml/dia com 9 g do extrato seco da planta), após a administração deste por 15 semanas e, finalmente após 12 semanas sem o uso (período de \"Wash out\"). Utilizamos o teste ANOVA e o teste de Tukey para comparação entre os períodos do estudo. O nível de significância considerado foi de 5%. Resultados: Trinta e seis pacientes (64%) eram mulheres. A média de idade dos 56 pacientes foi 44,1±9,16 anos. O IMC médio foi 27,2±4,4 Kg/m2. Não se observou alteração nos parâmetros antropométricos, séricos, no volume urinário ou efeitos adversos significativos durante todo o período de estudo. Houve redução da pressão arterial diastólica de 76±10,5 para 72,5±10,5 mmHg (p=0,02), quando comparado o período de uso do chá e o período de \"Wash out\". Aumento significativo dos valores do potássio urinário de 50,5±20,4 para 56,2±21,8 mEq/vol.24h (p=0,017); da relação magnésio/creatinina de 58±22,5 para 69,1±28,6 mEq/gCr.24h (p=0,013) e da relação potássio/creatinina, de 39,3±15,1 para 51,3±34,7 mEq/gCr.24h (p=0,008) foi observado ao final do período de uso do chá quando comparado com a avaliação inicial. O número de cálculos renais por paciente reduziu de 3,21±2,02 para 2,02±2,07 cálculos (p < 0,001) após o consumo do P. niruri quando comparado com o momento inicial. Na avaliação inicial, 24 pacientes apresentaram hipercalciúria e hipocitratúria (42,8%), seis apresentaram hiperuricosúria (10,7%) e cinco hiperoxalúria (8,9%). Após o uso do P. niruri, nos pacientes portadores de hiperuricosúria houve redução de 0,77±0,22 para 0,54±0,07 mg/vol.24h (p=0,0057) no valor do ácido úrico urinário. Nos portadores de hipocitratúria, o citrato urinário aumentou de 211,8±123,7 para 322,3±145,8 mg/vol.24h (p=0,0282) e nos pacientes com hiperoxalúria houve a redução no oxalato urinário de 59,0±11,7 para 28,8±16,0 mg/vol.24h (p=0,0002). Conclusão: O consumo do P. niruri se mostrou seguro e não provocou efeitos adversos ou alterações séricas relevantes e elevou a excreção urinária de magnésio e potássio. Algumas alterações metabólicas urinárias predisponentes a formação de cálculos normalizaram em subgrupos de pacientes estudados. O consumo do P. niruri contribuiu na eliminação de cálculos urinários / Introduction: Phyllanthus niruri (P. niruri) or breake-stone is a plant commonly used to reduce stone risk, however, clinical studies on this issue are lacking. The aim of this study was to prospectively evaluate the effects of P. niruri in metabolic parameters of patients with kidney stones and secondarily to evaluate the impact of the plant intake in the elimination of urinary calculi. Material and Methods: We studied 56 patients with kidney stones < 10 mm. Clinical, metabolic, and imaging studies were performed prior to P. niruri (tea infusion of 500 ml/day with 9 g of the dried plant extract), after 15 weeks of tea administration and finally after 12 weeks without the intake plant (wash out). ANOVA test for repeated measures and Tukey test and McNemars test for categorial variables. The significance level was set at 5%. Results: Thirty-six patients (64%) were female and mean age was 44.1±9.16 years-old. The mean BMI was 27.2±4.4 Kg/m2. There was no change in anthropometric and serum parameters or urinary volume throughout the study period. There was a reduction in diastolic blood pressure from 76±10.5 during the tea use to 72.5±10.5 mmHg after the wash out (p=0.02). When the tea use period was compared to the baseline assessment, there was a significant increase in urinary potassium from 50.5±20.4 to 56.2±21.8 mg/24-hour (p=0.017), magnesium/creatinine ratio from 58±22.5 to 69.1±28.6 mg/gCr24-hour (p=0.013) and potassium/creatinine ratio from 39.3±15.1 to 51.3±34.7 mg/gCr24-hour (p=0.008). The number of kidney stones per patient decreased from 3.21±2.02 to 2.02±2.07 calculi (p < 0.001) after consumption of tea compared with the initial stage. Initial evaluation showed hypercalciuria and hypocitraturia in 24 patients (42.8%), hyperuricosuria in six (10.7%) and hyperoxaluria in five cases (8.9%). In patients with hyperuricosuria there was a decrease in the amount of urinary uric acid from 0.77±0.22 to 0.54±0.07 mg/24-hour (p=0.0057). After the use of P. niruri, in patients with hypocitraturia, urinary citrate increased from 211.8±123.7 to 322.3±145.8 mg/24-hour (p=0.0282). In patients with hyperoxaluria there was a reduction in urinary oxalate from 59.0±11.7 to 28.8±16.0 mg/24-hour (p=0.0002). Conclusion: P. niruri intake is safe and does not cause significant adverse effects or significative serum metabolic changes. The use of the tea plant increases urinary excretion of magnesium and potassium. Some urinary metabolic changes predisposing to the formation of calculi normalized in subgroups of patients studied. The consumption of P. niruri contributed to the elimination of urinary calculi

Introdução: O Phyllanthus niruri (P. niruri) ou quebra pedra é uma planta com ação antilitogênica. No entanto, estudos clínicos nesta área ainda são escassos na literatura. O objetivo principal deste estudo foi avaliar prospectivamente os efeitos do P. niruri nos parâmetros metabólicos de pacientes com litíase urinária e, secundariamente, avaliar o impacto da ingestão do chá da planta na eliminação de cálculos urinários. Material e Métodos: Foram estudados 56 pacientes portadores de cálculos renais <10 mm. Avaliação clínica, metabólica e ultrassonográfica do trato urinário foram realizadas antes do uso do P. niruri (infusão de 500 ml/dia com 9 g do extrato seco da planta), após a administração deste por 15 semanas e, finalmente após 12 semanas sem o uso (período de \"Wash out\"). Utilizamos o teste ANOVA e o teste de Tukey para comparação entre os períodos do estudo. O nível de significância considerado foi de 5%. Resultados: Trinta e seis pacientes (64%) eram mulheres. A média de idade dos 56 pacientes foi 44,1±9,16 anos. O IMC médio foi 27,2±4,4 Kg/m2. Não se observou alteração nos parâmetros antropométricos, séricos, no volume urinário ou efeitos adversos significativos durante todo o período de estudo. Houve redução da pressão arterial diastólica de 76±10,5 para 72,5±10,5 mmHg (p=0,02), quando comparado o período de uso do chá e o período de \"Wash out\". Aumento significativo dos valores do potássio urinário de 50,5±20,4 para 56,2±21,8 mEq/vol.24h (p=0,017); da relação magnésio/creatinina de 58±22,5 para 69,1±28,6 mEq/gCr.24h (p=0,013) e da relação potássio/creatinina, de 39,3±15,1 para 51,3±34,7 mEq/gCr.24h (p=0,008) foi observado ao final do período de uso do chá quando comparado com a avaliação inicial. O número de cálculos renais por paciente reduziu de 3,21±2,02 para 2,02±2,07 cálculos (p < 0,001) após o consumo do P. niruri quando comparado com o momento inicial. Na avaliação inicial, 24 pacientes apresentaram hipercalciúria e hipocitratúria (42,8%), seis apresentaram hiperuricosúria (10,7%) e cinco hiperoxalúria (8,9%). Após o uso do P. niruri, nos pacientes portadores de hiperuricosúria houve redução de 0,77±0,22 para 0,54±0,07 mg/vol.24h (p=0,0057) no valor do ácido úrico urinário. Nos portadores de hipocitratúria, o citrato urinário aumentou de 211,8±123,7 para 322,3±145,8 mg/vol.24h (p=0,0282) e nos pacientes com hiperoxalúria houve a redução no oxalato urinário de 59,0±11,7 para 28,8±16,0 mg/vol.24h (p=0,0002). Conclusão: O consumo do P. niruri se mostrou seguro e não provocou efeitos adversos ou alterações séricas relevantes e elevou a excreção urinária de magnésio e potássio. Algumas alterações metabólicas urinárias predisponentes a formação de cálculos normalizaram em subgrupos de pacientes estudados. O consumo do P. niruri contribuiu na eliminação de cálculos urinários / Introduction: Phyllanthus niruri (P. niruri) or breake-stone is a plant commonly used to reduce stone risk, however, clinical studies on this issue are lacking. The aim of this study was to prospectively evaluate the effects of P. niruri in metabolic parameters of patients with kidney stones and secondarily to evaluate the impact of the plant intake in the elimination of urinary calculi. Material and Methods: We studied 56 patients with kidney stones < 10 mm. Clinical, metabolic, and imaging studies were performed prior to P. niruri (tea infusion of 500 ml/day with 9 g of the dried plant extract), after 15 weeks of tea administration and finally after 12 weeks without the intake plant (wash out). ANOVA test for repeated measures and Tukey test and McNemars test for categorial variables. The significance level was set at 5%. Results: Thirty-six patients (64%) were female and mean age was 44.1±9.16 years-old. The mean BMI was 27.2±4.4 Kg/m2. There was no change in anthropometric and serum parameters or urinary volume throughout the study period. There was a reduction in diastolic blood pressure from 76±10.5 during the tea use to 72.5±10.5 mmHg after the wash out (p=0.02). When the tea use period was compared to the baseline assessment, there was a significant increase in urinary potassium from 50.5±20.4 to 56.2±21.8 mg/24-hour (p=0.017), magnesium/creatinine ratio from 58±22.5 to 69.1±28.6 mg/gCr24-hour (p=0.013) and potassium/creatinine ratio from 39.3±15.1 to 51.3±34.7 mg/gCr24-hour (p=0.008). The number of kidney stones per patient decreased from 3.21±2.02 to 2.02±2.07 calculi (p < 0.001) after consumption of tea compared with the initial stage. Initial evaluation showed hypercalciuria and hypocitraturia in 24 patients (42.8%), hyperuricosuria in six (10.7%) and hyperoxaluria in five cases (8.9%). In patients with hyperuricosuria there was a decrease in the amount of urinary uric acid from 0.77±0.22 to 0.54±0.07 mg/24-hour (p=0.0057). After the use of P. niruri, in patients with hypocitraturia, urinary citrate increased from 211.8±123.7 to 322.3±145.8 mg/24-hour (p=0.0282). In patients with hyperoxaluria there was a reduction in urinary oxalate from 59.0±11.7 to 28.8±16.0 mg/24-hour (p=0.0002). Conclusion: P. niruri intake is safe and does not cause significant adverse effects or significative serum metabolic changes. The use of the tea plant increases urinary excretion of magnesium and potassium. Some urinary metabolic changes predisposing to the formation of calculi normalized in subgroups of patients studied. The consumption of P. niruri contributed to the elimination of urinary calculi

Thymic epithelial cells (TECs) are the main component of the thymic stroma, which supports T-cell proliferation and repertoire selection. Here, we demonstrate that Cbx4, a Polycomb protein that is highly expressed in the thymic epithelium, has an essential and non-redundant role in thymic organogenesis. Targeted disruption of Cbx4 causes severe hypoplasia of the fetal thymus as a result of reduced thymocyte proliferation. Cell-specific deletion of Cbx4 shows that the compromised thymopoiesis is rooted in a defective epithelial compartment. Cbx4-deficient TECs exhibit impaired proliferative capacity, and the limited thymic epithelial architecture quickly deteriorates in postnatal mutant mice, leading to an almost complete blockade of T-cell development shortly after birth and markedly reduced peripheral T-cell populations in adult mice. Furthermore, we show that Cbx4 physically interacts and functionally correlates with p63, which is a transcriptional regulator that is proposed to be important for the maintenance of the stemness of epithelial progenitors. Together, these data establish Cbx4 as a crucial regulator for the generation and maintenance of the thymic epithelium and, hence, for thymocyte development.

O objetivo deste estudo foi estabelecer uma correlação entre o efeito da suplementação por meio da ingestão de castanhas-do-brasil (CS) com o estado nutricional de praticantes de capoeira em relação ao selênio (Se). A importância deste micronutriente foi evidenciada pela sua participação no sistema de proteção antioxidante, justificada pela incorporação de Se na glutationa peroxidase (E. C. 1.11.1.9). Esta enzima catalisa a redução de hidroperóxidos e facilita a conversão de H2O2, protegendo o organismo contra o dano oxidativo, e outros efeitos prejudiciais das espécies reativas de oxigênio (ROS). A atividade física proporciona um aumento no consumo de O2 e consequentemente maior produção de ROS, provocando estresse oxidativo. A pesquisa foi composta por 29 capoeiristas, residentes em São Paulo, com idade média de 21 anos para mulheres, e 24 para homens. O período médio de treinamento foi de 3,51 por semana e a duração de cada treinamento em média, foi de 109 minutes. O consumo médio de oxigênio (VO2 Máx.) foi de 41 ml/kg/min para as mulheres, e 48mllkg/min para os homens. A classificação do estado nutricional dos capoeiristas, de acordo com seu IMC foi normal (Organização Mundial de Saúde, 1995). Antes da suplementação, a ingestão usual de Se dos capoeiristas foi insatisfatória de acordo com a EAR e RDA. A concentração de Se no plasma e eritrócito aumentou depois da suplementação com CS (p<0,05), mas não houve correlação com o sexo dos participantes. A atividade enzimática da GPx também aumentou após a suplementação (p<0,05), demonstrando que a enzima é um sensível indicador do estado nutricional de Se, e não houve correlação em relação ao sexo dos participantes. Os resultados sugerem uma correlação positiva entre o efeito da suplementacão com CS e a concentração de Se e da atividade da enzima GPx (p< 0,05; R=0,72 para o plasma and R=85 para o eritrócito). / The purpose of this study was to establish a correlation between the effect of supplementation with Brazilian nuts (BN) with the nutritional status of Se and it\'s activity in young adult capoeira players. The biological importance of this oligoelement was evident by the participation in the \"antioxidant protection system\". It\'s antioxidant role is justified by its incorporation, as selenium, in the peroxidase glutathione (E.C. 1.11.1.9). This enzyme catalyzes the reduction of organic hidroperoxides and facilitates the conversion of H2O2 protecting the organism against the oxidative damage, and other harmful effects of \"reactive oxygen species\" (ROS). The physical activity causes an increase in consumption of O2 and consequently high production of ROS, causing oxidative stress. The population has composed of 29 capoeira players resident in São Paulo, with a mean age of 21 women and 24 for men. The average training period was 3,51 per week and the duration of each training period was 109,46 minutes. The average oxygen consumption (VO2 Máx., ml/kg/min) was 41 for women and 48 for men. Nutritional status classification of the capoeira players (cap) according with World Health Organization (WHO): IMC (1995) was normal. Before supplementation the usual diet was unsatisfactory for selenium according to EAR and RDA (2000). The Se concentration of the plasma and erythrocyte increased after supplementation with Brazilian nuts (p< 0,05), but didn\'t correlated with the sex of the participants. GSH-Px enzymatic activity also increased after this supplementation (p< 0,05), showing that this enzyme is a sensitive marker of nutritional status of Se. Also we didn\'t found correlation with the sex of the participants. The results suggest a positive correlation between the effect of supplementation with BN and Se concentrations and the activity of the GSH-Px enzyme (p< 0,05; R=0,72 for the plasma and R=85 for the erythrocyte).

O objetivo deste estudo foi estabelecer uma correlação entre o efeito da suplementação por meio da ingestão de castanhas-do-brasil (CS) com o estado nutricional de praticantes de capoeira em relação ao selênio (Se). A importância deste micronutriente foi evidenciada pela sua participação no sistema de proteção antioxidante, justificada pela incorporação de Se na glutationa peroxidase (E. C. 1.11.1.9). Esta enzima catalisa a redução de hidroperóxidos e facilita a conversão de H2O2, protegendo o organismo contra o dano oxidativo, e outros efeitos prejudiciais das espécies reativas de oxigênio (ROS). A atividade física proporciona um aumento no consumo de O2 e consequentemente maior produção de ROS, provocando estresse oxidativo. A pesquisa foi composta por 29 capoeiristas, residentes em São Paulo, com idade média de 21 anos para mulheres, e 24 para homens. O período médio de treinamento foi de 3,51 por semana e a duração de cada treinamento em média, foi de 109 minutes. O consumo médio de oxigênio (VO2 Máx.) foi de 41 ml/kg/min para as mulheres, e 48mllkg/min para os homens. A classificação do estado nutricional dos capoeiristas, de acordo com seu IMC foi normal (Organização Mundial de Saúde, 1995). Antes da suplementação, a ingestão usual de Se dos capoeiristas foi insatisfatória de acordo com a EAR e RDA. A concentração de Se no plasma e eritrócito aumentou depois da suplementação com CS (p<0,05), mas não houve correlação com o sexo dos participantes. A atividade enzimática da GPx também aumentou após a suplementação (p<0,05), demonstrando que a enzima é um sensível indicador do estado nutricional de Se, e não houve correlação em relação ao sexo dos participantes. Os resultados sugerem uma correlação positiva entre o efeito da suplementacão com CS e a concentração de Se e da atividade da enzima GPx (p< 0,05; R=0,72 para o plasma and R=85 para o eritrócito). / The purpose of this study was to establish a correlation between the effect of supplementation with Brazilian nuts (BN) with the nutritional status of Se and it\'s activity in young adult capoeira players. The biological importance of this oligoelement was evident by the participation in the \"antioxidant protection system\". It\'s antioxidant role is justified by its incorporation, as selenium, in the peroxidase glutathione (E.C. 1.11.1.9). This enzyme catalyzes the reduction of organic hidroperoxides and facilitates the conversion of H2O2 protecting the organism against the oxidative damage, and other harmful effects of \"reactive oxygen species\" (ROS). The physical activity causes an increase in consumption of O2 and consequently high production of ROS, causing oxidative stress. The population has composed of 29 capoeira players resident in São Paulo, with a mean age of 21 women and 24 for men. The average training period was 3,51 per week and the duration of each training period was 109,46 minutes. The average oxygen consumption (VO2 Máx., ml/kg/min) was 41 for women and 48 for men. Nutritional status classification of the capoeira players (cap) according with World Health Organization (WHO): IMC (1995) was normal. Before supplementation the usual diet was unsatisfactory for selenium according to EAR and RDA (2000). The Se concentration of the plasma and erythrocyte increased after supplementation with Brazilian nuts (p< 0,05), but didn\'t correlated with the sex of the participants. GSH-Px enzymatic activity also increased after this supplementation (p< 0,05), showing that this enzyme is a sensitive marker of nutritional status of Se. Also we didn\'t found correlation with the sex of the participants. The results suggest a positive correlation between the effect of supplementation with BN and Se concentrations and the activity of the GSH-Px enzyme (p< 0,05; R=0,72 for the plasma and R=85 for the erythrocyte).

Fibroblast growth factor receptors (FGFR) play key roles in proliferation, differentiation, and tumorigenesis. Many urothelial carcinomas contain activating point mutations or increased expression of FGFR3. However, little is known about the role of other FGFRs. We examined FGFR expression in telomerase-immortalized normal human urothelial cells, urothelial carcinoma cell lines, and tumor samples and showed that FGFR1 expression is increased in a high proportion of cell lines and tumors independent of stage and grade. To determine the role of FGFR1 in low-stage bladder cancer, we overexpressed FGFR1 in telomerase-immortalized normal human urothelial cells and examined changes in proliferation and cell survival in response to FGF2. FGFR1 stimulation increased proliferation and reduced apoptosis. To elucidate the mechanistic basis for these alterations, we examined the signaling cascades activated by FGFR1. FRS2alpha and PLCgamma were activated in response to FGF2, leading to activation of the mitogen-activated protein kinase pathway. The level of mitogen-activated protein kinase activation correlated with the level of cyclin D1, MCL1, and phospho-BAD, which also correlated with FGFR-induced proliferation and survival. Knockdown of FGFR1 in urothelial carcinoma cell lines revealed differential FGFR1 dependence. JMSU1 cells were dependent on FGFR1 expression for survival but three other cell lines were not. Two cell lines (JMSU1 and UMUC3) were dependent on FGFR1 for growth in soft agar. Only one of the cell lines tested (UMUC3) was frankly tumorigenic; here, FGFR1 knockdown inhibited tumor growth. Our results indicate that FGFR1 has significant effects on urothelial cell phenotype and may represent a useful therapeutic target in some cases of urothelial carcinoma.