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Background The dietary management of methylmalonic acidaemia (MMA) is a low-protein diet providing sufficient energy to avoid catabolism and to limit production of methylmalonic acid. The goal is to achieve normal growth, good nutritional status and the maintenance of metabolic stability. Aim To describe the dietary management of patients with MMA across Europe. Methods A cross-sectional questionnaire was sent to European colleagues managing inherited metabolic disorders (IMDs) (n=53) with 27 questions about the nutritional management of organic acidaemias. Data were analysed by different age ranges (0–6 months; 7–12 months; 1–10 years; 11–16 years; >16 years). Results Questionnaires were returned from 53 centres. Twenty-five centres cared for 80 patients with MMA vitamin B12 responsive (MMAB12r) and 43 centres managed 215 patients with MMA vitamin B12 non-responsive (MMAB12nr). For MMAB12r patients, 44% of centres (n=11/25) prescribed natural protein below the World Health Organization/Food and Agriculture Organization/United Nations University (WHO/FAO/UNU) 2007 safe levels of protein intake in at least one age range. Precursor-free amino acids (PFAA) were prescribed by 40% of centres (10/25) caring for 36% (29/80) of all the patients. For MMAB12nr patients, 72% of centres (n=31/43) prescribed natural protein below the safe levels of protein intake (WHO/FAO/UNU 2007) in at least one age range. PFAA were prescribed by 77% of centres (n=33/43) managing 81% (n=174/215) of patients. In MMAB12nr patients, 90 (42%) required tube feeding: 25 via a nasogastric tube and 65 via a gastrostomy. Conclusions A high percentage of centres used PFAA in MMA patients together with a protein prescription that provided less than the safe levels of natural protein intake. However, there was inconsistent practices across Europe. Long-term efficacy studies are needed to study patient outcome when using PFAA with different severities of natural protein restrictions in patients with MMA to guide future practice.

Orientador: Wilma De Grava Kempinas Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: Nos últimos anos vem aumentando o reconhecimento mundial sobre a relevância da nutrição como pilar básico para o desenvolvimento econômico e social. Em países em desenvolvimento como o Brasil, por exemplo, a desnutrição é um problema sócio-econômico causado pela má alimentação e pela baixa renda. O nascimento de crianças com baixo peso é reconhecido como um importante problema de saúde pública, com efeitos devastadores no desenvolvimento, na sobrevivência e na saúde humana. Milhares de crianças têm seu crescimento retardado pela má nutrição, no entanto poucos trabalhos relacionam a desnutrição protéica materna e o desenvolvimento do sistema reprodutor. Dessa forma, o presente trabalho teve por objetivo avaliar o impacto da desnutrição protéica in utero sobre parâmetros morfofuncionais do trato reprodutivo masculino em diferentes fases do desenvolvimento sexual: pré-puberal, peripuberal e adulta, assim como sobre a instalação da puberdade em filhotes fêmeas, utilizando o rato como modelo experimental. Para tanto, foram obtidas ratas prenhes e divididas em dois grupos experimentais: grupo que recebeu ração padrão (n=12, grupo RP, 17% de proteína) e grupo que recebeu ração hipoprotéica (n=16, grupo RH, 6% de proteína) durante toda a prenhez. Durante a lactação os dois grupos experimentais receberam ração padrão. No 20º dia gestacional, 10 ratas (grupo RP n=4, grupo RH n=6) foram sacrificadas procedendo-se em seguida a laparotomia para avaliação da performance reprodutiva das progenitoras. As demais ratas prenhes (grupo RP n=8, grupo RH, n=10) foram mantidas para permitir o nascimento e amamentação dos filhotes. A restrição protéica provocou redução do peso placentário, aumento do consumo de ração das progenitoras durante o início da gestação e redução deste consumo no final da gestação e início da lactação. No entanto, esta variação no consumo de ração não foi suficiente para compensar o efeito da dieta hipoprotéica sobre o organismo materno e fetal, uma vez que o ganho de peso das progenitoras durante a gestação e o peso dos filhotes nas diferentes fases do desenvolvimento apresentaram redução significativa. Os filhotes fêmeas do grupo RH tiveram aumento da distância anogenital, sugerindo um processo de masculinização do fenótipo feminino. Nos filhotes de ambos os sexos a restrição protéica in utero provocou atraso no início da puberdade. Nos filhotes machos a restrição protéica provocou redução do peso testicular na fase pré-puberal e no adulto provocou danos em alguns parâmetros morfofuncionais do sistema reprodutivo reduzindo o peso do ducto deferente, o número de células de Sertoli, a motilidade espermática, a produção diária de espermatozóides e a reserva espermática na cauda do epidídimo. Os níveis séricos de testosterona foram reduzidos em 27% quando comparado ao grupo RP. Por outro lado, a incidência de espermatozóides com anormalidades morfológicas e retenção de gota citoplasmática aumentou. Assim, conclui-se que a restrição protéica in utero, nestas condições experimentais, provocou restrição de crescimento, comprometeu o desenvolvimento sexual, atrasando o início da puberdade e provocando danos espermáticos no adulto. Abstract: In the past few years the worldwide recognition of the relevance of nutrition as a basis for social and economic development has been growing. In developing countries such as Brazil undernutrition is a socioeconomic problem caused by poor nutrition and low income. The birth of children with low birth weight is considered an important public health problem, with devastating effects on human development, survival and health. Although millions of children have their growth retarded due to poor nutrition, few works relate maternal proteic undernutrition to the development of the reproductive system. Thus, the objective of the present work was to evaluate the impact of in utero proteic undernutrition on morphofunctional endpoints in the male reproductive tract during the following phases of sexual development: prepubertal, peripubertal and adult, as well as on the installation of puberty in the female pups, utilizing the rat as the experimental model. For this, pregnant female rats were obtained and divided into two experimental groups: one treated with standard chow (SC, n=12, 17% protein) and the other treated with hypoproteic chow (HC, n=16, 6% protein) throughout gestation. During the lactation period the two groups received standard chow. On the 20th gestational day 10 rats (SC n=4, HC n=6) were sacrificed and laparotomy was performed to evaluate maternal reproductive performance. The remaining pregnant rats (SC n=8, HC n=10) were left to deliver and nurse the offspring. The proteic restriction provoked reduction in the placental weight, increase in the maternal chow consumption at the beginning of pregnancy and reduction at the end of pregnancy and beginning of lactation. However, this variation in the chow consumption was not sufficient to compensate for the hypoproteic effect on the maternal and fetal organisms, since the maternal weight gain over gestation and the weight of the pups in the different phases of the development were significantly reduced. The anogenital distance increased in the female pups of the HC group suggesting a process of masculinization of the female phenotype. In both sexes the in utero proteic restriction delayed pubertal installation. In the male offspring the proteic restriction caused reduction in the testicular weight at prepuberty and, at adulthood, damage to some of the morphofunctional endpoints of the reproductive system by reducing: the vas deferens weight, number of Sertoli cells, sperm motility, daily sperm production and sperm reserves in the epididymal cauda. Serum testosterone levels were lowered by 27% compared to the SC group. On the other hand, the incidence of sperm cells with morphological abnormalities and retention of the cytoplasmatic droplet increased. It was concluded that the proteic restriction in utero, in these experimental conditions, restricted growth, compromised the sexual development by delaying the beginning of puberty and leaded to damage in adulthood. Mestrado Biologia Celular Mestre em Biologia Celular e Estrutural

Orientador: Everardo Magalhães Carneiro Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: Os canais de cálcio voltagem-dependentes (CaV) são proteínas de membrana plasmática que conduzem cálcio, e são ativados pela despolarização da mesma promovendo influxo do íon, que serve como um segundo mensageiro intracelular, transformando sinais elétricos em químicos. Esse processo controla diversos eventos intracelulares, como exocitose, endocitose, contração muscular, transmissão sináptica e metabolismo. Em células beta (B), a secreção de insulina estimulada por glicose e/ou leucina ocorre por diversos sinais que levam à despolarização da membrana e influxo de cálcio, que age no processo de acoplamento estímulo/secreção dos grânulos contendo insulina. É possível a existência de efeitos sinérgicos entre o metabolismo da leucina e glicose, permitindo um controle fino da expressão gênica, produção e secreção de insulina em células B. Recentemente demonstramos que animais que sofreram um processo de restrição protéica modificam o mecanismo de secreção de insulina alterando a resposta secretória para diferentes secretagogos (glicose, aminoácidos, etc.). Nesse trabalho, buscamos elucidar o envolvimento dos íons cálcio nos processos de secreção de insulina, bem como avaliar a expressão gênica e protéica das subunidades alfa1 e beta2 do canal nos diferentes grupos estudados. Observamos uma redução na expressão gênica das duas subunidades do CaV em ilhotas de animais desnutridos e uma tendência de recuperação na expressão protéica da subunidade ?1 em animais desnutridos suplementados com leucina. As áreas abaixo das curvas (AUC) de cálcio das ilhotas não apresentaram diferença entre os grupos quando estimulados com alta (16,7 mM) glicose e 40 mM de K+, porém, há um aumento na área abaixo da curva quando estimuladas com tolbutamida no grupo desnutrido suplementado com leucina (LPL). As secreções de insulina frente a inibidores de canal de cálcio apresentaram resultados similares frente a alta glicose e tolbutamida, porém apresentando valores absolutos menores. Ilhotas provenientes de animais LPL apresentaram recuperação da taxa de liberação de insulina quando estimuladas com ácido ketoisocapróico, atingindo valores similares aos controles. Essa recuperação não foi observada quando estimulamos as ilhotas com cloreto de potássio. Observamos também uma redução na área das ilhotas de animais desnutridos, com recuperação a valores equivalentes aos controles quando há suplementação com leucina. Nossos dados sugerem que o manejo dos íons cálcio possa não estar diretamente envolvido na melhora da secreção de insulina por ilhotas de animais desnutridos suplementados com leucina, mesmo havendo uma melhora na expressão protéica da subunidade alpha1 do Cav em ilhotas de animais LPL, através de uma possível modulação pós-transcricional. Abstract: Voltage-dependent calcium channels (CaV) are plasma membrane proteins that lead calcium, and are activated by depolarization of the same by promoting the influx of this ion, which serves as an intracellular second messenger, turning electrical signals into chemical. This process controls several intracellular events such as exocytosis, endocytosis, muscle contraction, synaptic transmission and metabolism. In beta cells (B), insulin secretion stimulated by glucose and/or leucine occurs by several signs that lead to membrane depolarization and calcium influx, which acts on the coupling process stimulus/secretion of granules containing insulin. It is possible that there are synergistic effects between the metabolism of glucose and leucine, allowing fine control of gene expression, production and insulin secretion in B cells. We have shown that animals which have undergone a process of protein restriction alter the mechanism of insulin secretion by altering the secretory response to different secretagogues (glucose, amino acids, etc.). In this paper we elucidate the involvement of calcium ions in the process of insulin secretion, as well assess the gene and protein expression of alpha1 and beta2 subunits of the channel in different groups. Observed a decrease in gene expression of two subunits of CaV in islets of malnourished animals and a recovery trend in protein expression of ?1 subunit in malnourished animals supplemented with leucine. The areas under the curve (AUC) for calcium of islets did not differ between groups when stimulated with high (16.7 mM) glucose and 40 mM K +, however, there is an increase in area under the curve when stimulated with tolbutamide in undernourished group supplemented with leucine (LPL). The secretions of insulin compared to calcium channel inhibitors showed similar results compared to high glucose and tolbutadima, although a smaller absolute values. Islets from LPL animals showed recovery of the rate of insulin release when stimulated with ketoisocaproic acid (KIC), reaching values similar to controls. This recovery was not observed when we stimulate the islets with potassium chloride. We also observed a reduction in the area of the islets of malnourished animals, with recovery to similar values for controls when supplementation with leucine. Our data suggest that the management of calcium ions can not be directly involved the improvement of insulin secretion by islets of malnourished animals supplemented with leucine, even with an improvement in protein expression of the alpha1 subunit of the Cav in islets of animals LPL, through a possible post-transcriptional modulation. Mestrado Fisiologia Mestre em Biologia Funcional e Molecular

Background : A very low protein diet (VLPD) with ketoacid analogs of essential amino acids (KA/EAA) administration can remarkably influence protein synthesis and metabolic disturbances of patients with advanced chronic kidney disease (CKD), and may also slow the decline in renal function. Methods : A retrospective cohort study was carried out to monitor renal progression and metabolic and nutritional status among 140 patients with CKD stage III or IV. One group (n = 70) was on a low protein diet (LPD) with 0.6 g of protein intake, and another group (n = 70) was on a VLPD with 0.3 g of protein and KA/EAA supplementation of 100 mg/kg/day for 12 months. Results : At 12-month follow-up, estimated glomerular filtration rate (GFR) significantly decreased from 41.6 ± 10.2 to 36.4 ± 8.8 mL/min/1.73 m2 (P < 0.001) and urine protein increased from 0.6 ± 0.5 to 0.9 ± 1.1 g/day (P = 0.017) in the LPD group, but no significant changes in estimated GFR and urine protein were found in the VLPD plus KA/EAA group. A significant mean difference in rate of change in estimated GFR (−5.2 ± 3.6 mL/min/1.73 m2 per year; P < 0.001) was observed between the two groups. After Cox regression analysis, treatment with VLPD plus KA/EAA significantly protected against the incidence of declining GFR > 10% annually (adjusted hazard ratio, 0.42; 95% confidence interval, 0.23-0.79; P = 0.006) and significant correlations were found between using VLPD plus KA/EEA and increased GFR. Conclusion : VLPD supplementation with KA/EAA is associated with delayed renal progression while preserving the nutritional status in the patients with CKD. Co-administration of VLPD and KA/EAA may prove an effective alternative to conservative management of CKD.

This experiment was conducted to investigate the effects of branched-chain amino acids (BCAA) supplemented in protein-restricted diets on the growth performance and the expression profile of amino acid transporters and energy metabolism related regulators in the white adipose tissue (WAT) of different regional depots including dorsal subcutaneous adipose (DSA) and abdominal subcutaneous adipose (ASA). A total of 24 crossbred barrows (7.40 ± 0.70 kg) were randomly divided into 4 groups and were fed the following isocaloric diets for 33 days: 1) a recommended adequate protein diet (AP, 20% CP, as a positive control); 2) a low protein diet (LP, 17% CP); 3) the LP diet supplemented with BCAA (LP + B, 17% CP) to reach the same level of the AP diet group; 4) the LP diet supplemented with 2 times the amount of BCAA (LP + 2B, 17% CP). The daily gain and daily feed intake of the LP diet group were the lowest among all the treatments (P 0.05). Moreover, BCAA supplementation down-regulated the expression levels of amino acid transporters including L-type amino acid transporter 1 and sodium-coupled neutral amino acid transporter 2 in DSA, but up-regulated the expression level of L-type amino acid transporter 4 in ASA (P

Intrauterine malnutrition predisposes the offspring towards the development of type 2 diabetes and cardiovascular disease. To explain this association, the Developmental Origins of Health and Disease (DOHaD) hypothesis was introduced, meaning that subtle environmental changes during embryonic and fetal development can influence postnatal physiological functions. Different mechanisms, including epigenetics, are thought to be involved in this fetal programming, but the link between epigenetics and disease is missing. There is increasing evidence that ectopic lipid accumulation and/or lipotoxicity is induced by fetal programming. The aim of this review is to provide insights into the mechanisms underlying lipotoxicity through programming which contributes to the increase in hepatic and cardiac metabolic risk. This article is protected by copyright. All rights reserved.

Intrauterine malnutrition predisposes the offspring towards the development of type 2 diabetes and cardiovascular disease. To explain this association, the Developmental Origins of Health and Disease hypothesis was introduced, meaning that subtle environmental changes during embryonic and foetal development can influence post-natal physiological functions. Different mechanisms, including epigenetics, are thought to be involved in this foetal programming, but the link between epigenetics and disease is missing. There is increasing evidence that ectopic lipid accumulation and/or lipotoxicity is induced by foetal programming. The aim of this review is to provide insights into the mechanisms underlying lipotoxicity through programming, which contributes to the increase in hepatic and cardiac metabolic risk.

Substantial evidence links early postnatal nutrition to the development of obesity later in life. However, the molecular mechanisms of this connection must be further elucidated. Epigenetic mechanisms have been indicated to be involved in this process, referred to as metabolic programming. Therefore, we propose here that early postnatal nutrition (breast and formula feeding) epigenetically programs the developing organs via modulation of the gut microbiome and influences the body weight phenotype including the predisposition to obesity. Specifically, the early-age food patterns are known to determine the gross composition of the early gut microbiota. In turn, the microbiota produces large quantities of epigenetically active metabolites, such as folate and short chain fatty acids (butyrate and acetate). The spectrum of these produced metabolites depends on the composition of the gut microbiota. Hence, it is likely that changes in gut microbiota that result in altered metabolite composition might influence the epigenome of directly adjacent intestinal cells, as well as other major target cell populations, such as hepatocytes and adipocytes. Nuclear receptors and other transcription factors (the PPARs, LXR, RXR, and others) could be physiologically relevant targets of this metabolite-induced epigenetic regulation. Ultimately, transcriptional networks regulating energy balance could be manipulated. For these reasons, we postulate that early nutrition may influence the baby epigenome via microbial metabolites, which contributes to the observed relationship between early nutrition and adult obesity.

Nutrition plays a key role in many aspects of health and dietary imbalances are major determinants of chronic diseases including cardiovascular disease, obesity, diabetes and cancer. Adequate nutrition is particularly essential during critical periods in early life (both pre- and postnatal). In this regard, there is extensive epidemiologic and experimental data showing that early sub-optimal nutrition can have health consequences several decades later.The hypothesis that epigenetic mechanisms may link such nutritional imbalances with altered disease risk has been gaining acceptance over recent years. Epigenetics can be defined as the study of heritable changes in gene expression that do not involve alterations in the DNA sequence. Epigenetic marks include DNA methylation, histone modifications and a variety of non-coding RNAs. Strikingly, they are plastic and respond to environmental signals, including diet. Here we will review how dietary factors modulate the establishment and maintenance of epigenetic marks, thereby influencing gene expression and, hence, disease risk and health. (C) 2012 Elsevier Masson SAS. All rights reserved.

Introducción: El tratamiento de las enfermedades renales, que son un grave problema de salud pública, es muy complicado. La terapia nutrimental busca retardar la progresión de la enfermedad, mantener un buen estado nutricio y prevenir el desarrollo de comorbilidades. Objetivo: El objetivo del presente estudio fue analizar diez especies de pescado de consumo cotidiano para identificar aquellas que por su bajo aporte de fósforo, proteína de alto valor biológico y su aporte de ácidos grasos n-3 puedan incluirse en la dieta del paciente renal. Material y métodos: Se analizaron las siguientes especies: Bonito, Cabezona, Chucho, Escolar, Espada, Golondrina, Lenguado, Lobina, Mojarra rayada y Pámpano, siguiendo las técnicas de la AOAC y Keller, para determinar su contenido de proteína, fósforo, sodio, potasio, colesterol, vitaminas D3 y E y ácidos grasos n-3 EPA + DHA. Posteriormente se evaluaron las relaciones entre estos nutrimentos. Resultados: Las especies analizadas presentaron valores de proteína desde 16,5 g/100 g de filete (Lobina) hasta 27,2 g/100 g (Cabezona), el valor de fósforo más bajo fue de 28,6 mg/100 g (Mojarra rayada) y el más alto fue 216,3 mg/100 g (Chucho). 80% de las especies presentaron > 100 mg EPA + DHA en 100 g de filete. Por su relación Fósforo/g Proteína todos los pescados excepto Escolar y Espada, pueden incluirse; la relación más baja de fósforo/EPA + DHA se presentó en Bonito, Escolar, Golondrina, Lobina, Mojarra rayada. Conclusiones: El Pámpano es la especie más recomendada para los pacientes renales por las relaciones entre todos sus nutrimentos; aunque todas las especies, excepto Escolar y Espada, pueden formar parte de la alimentación renal.Introduction: Medical and nutritional treatment for renal disease, now a major public health issue, is highly complicated. Nutritional therapy must seek to retard renal dysfunction, maintain an optimal nutritional status and prevent the development of underlying pathologies. Objective: To analyze ten fish species to identify those that, because of their low phosphorus content, high biological value protein and elevated n-3 fatty acids EPA and DHA, could be included in renal patient's diet. Materials and methods: The following fish species (Litte tunny, Red drum, Spotted eagleray, Escolar, Swordfish, Big-scale pomfret, Cortez flounder, Largemouth blackbass, Periche mojarra, Florida Pompano) were analyzed according to the AOAC and Keller techniques to determine their protein, phosphorus, sodium, potassium, cholesterol, vitamins D3 and E, and n-3 EPA+DHA content. These results were used to calculate relations between nutrients. Results: The protein in the analyzed species ranged from 16.5 g/100 g of fillet (Largemouth black bass) to 27.2 g/100 g (Red drum); the lowest phosphorus value was 28.6 mg/100 g (Periche mojarra) and the highest 216.3 mg/100 g (Spotted eagle ray). 80% of the fish presented > 100 mg EPA + DHA in 100 g of fillet. By its Phosphorus/gProtein ratio, Escolar and Swordfish could not be included in the renal diet; Little tunny, Escolar, Big-scale pomfret, Largemouth black-bass, Periche mojarra and Florida Pompano presented a lower Phosphorus/EPA + DHA ratio. Conclusions: Florida pompano is the most recommended specie for renal patients, due to its optimal nutrient relations. However, all analyzed species, except Escolar and Swordfish, could be included in renal diets.

Introducción: El tratamiento de las enfermedades renales, que son un grave problema de salud pública, es muy complicado. La terapia nutrimental busca retardar la progresión de la enfermedad, mantener un buen estado nutricio y prevenir el desarrollo de comorbilidades. Objetivo: El objetivo del presente estudio fue analizar diez especies de pescado de consumo cotidiano para identificar aquellas que por su bajo aporte de fósforo, proteína de alto valor biológico y su aporte de ácidos grasos n-3 puedan incluirse en la dieta del paciente renal. Material y métodos: Se analizaron las siguientes especies: Bonito, Cabezona, Chucho, Escolar, Espada, Golondrina, Lenguado, Lobina, Mojarra rayada y Pámpano, siguiendo las técnicas de la AOAC y Keller, para determinar su contenido de proteína, fósforo, sodio, potasio, colesterol, vitaminas D3 y E y ácidos grasos n-3 EPA + DHA. Posteriormente se evaluaron las relaciones entre estos nutrimentos. Resultados: Las especies analizadas presentaron valores de proteína desde 16,5 g/100 g de filete (Lobina) hasta 27,2 g/100 g (Cabezona), el valor de fósforo más bajo fue de 28,6 mg/100 g (Mojarra rayada) y el más alto fue 216,3 mg/100 g (Chucho). 80% de las especies presentaron > 100 mg EPA + DHA en 100 g de filete. Por su relación Fósforo/g Proteína todos los pescados excepto Escolar y Espada, pueden incluirse; la relación más baja de fósforo/EPA + DHA se presentó en Bonito, Escolar, Golondrina, Lobina, Mojarra rayada. Conclusiones: El Pámpano es la especie más recomendada para los pacientes renales por las relaciones entre todos sus nutrimentos; aunque todas las especies, excepto Escolar y Espada, pueden formar parte de la alimentación renal. Introduction: Medical and nutritional treatment for renal disease, now a major public health issue, is highly complicated. Nutritional therapy must seek to retard renal dysfunction, maintain an optimal nutritional status and prevent the development of underlying pathologies. Objective: To analyze ten fish species to identify those that, because of their low phosphorus content, high biological value protein and elevated n-3 fatty acids EPA and DHA, could be included in renal patient's diet. Materials and methods: The following fish species (Litte tunny, Red drum, Spotted eagleray, Escolar, Swordfish, Big-scale pomfret, Cortez flounder, Largemouth blackbass, Periche mojarra, Florida Pompano) were analyzed according to the AOAC and Keller techniques to determine their protein, phosphorus, sodium, potassium, cholesterol, vitamins D3 and E, and n-3 EPA+DHA content. These results were used to calculate relations between nutrients. Results: The protein in the analyzed species ranged from 16.5 g/100 g of fillet (Largemouth black bass) to 27.2 g/100 g (Red drum); the lowest phosphorus value was 28.6 mg/100 g (Periche mojarra) and the highest 216.3 mg/100 g (Spotted eagle ray). 80% of the fish presented > 100 mg EPA + DHA in 100 g of fillet. By its Phosphorus/gProtein ratio, Escolar and Swordfish could not be included in the renal diet; Little tunny, Escolar, Big-scale pomfret, Largemouth black-bass, Periche mojarra and Florida Pompano presented a lower Phosphorus/EPA + DHA ratio. Conclusions: Florida pompano is the most recommended specie for renal patients, due to its optimal nutrient relations. However, all analyzed species, except Escolar and Swordfish, could be included in renal diets.

Nutrition plays a key role in many aspects of health and dietary imbalances are major determinants of chronic diseases including cardiovascular disease, obesity, diabetes and cancer. Adequate nutrition is particularly essential during critical periods in early life (both pre- and postnatal). In this regard, there is extensive epidemiologic and experimental data showing that early sub-optimal nutrition can have health consequences several decades later. The hypothesis that epigenetic mechanisms may link such nutritional imbalances with altered disease risk has been gaining acceptance over recent years. Epigenetics can be defined as the study of heritable changes in gene expression that do not involve alterations in the DNA sequence. Epigenetic marks include DNA methylation, histone modifications and a variety of non-coding RNAs. Strikingly, they are plastic and respond to environmental signals, including diet. Here we will review how dietary factors modulate the establishment and maintenance of epigenetic marks, thereby influencing gene expression and, hence, disease risk and health. (C) 2012 Elsevier Masson SAS. All rights reserved.

It has been well documented that different therapeutic strategies, including angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs, and dietary protein restriction, lower urinary protein excretion in patients with diabetic and non-diabetic nephropathy. Experimental evidence suggests that this antiproteinuric effect is, at least in part, related to a reduction in the glomerular capillary hydraulic pressure. ACE inhibitors appear to achieve this reduction in glomerular capillary pressure, mainly through a fall in postglomerular arteriolar resistance, whereas dietary protein restriction and non-steroidal antiinflammatory drugs appear to invoke the response predominantly through an increase in preglomerular resistance. This leads to the suggestion that both ''glomerular preload reduction'' (afferent vasoconstriction) and ''glomerular afterload reduction'' (efferent vasodilation) will result in an antiproteinuric response. Interestingly, these same therapeutic regimens, particularly the ACE inhibitors and low-protein diets, have been proven to prevent progressive glomerulosclerosis in animal models. This concept of influencing glomerular hemodynamics both at the afferent and efferent arteriolar level may open new perspectives in the treatment of patients with renal protein loss and renal failure. At present, however, it is too early to conclude whether the fall in proteinuria induced by these treatments will also contribute to a better renal survival of these patients.

Orientador: Everardo Magalhães Carneiro Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: A desnutrição ainda é um problema de saúde pública que afeta principalmente países em desenvolvimento e sua prevalência chega a ser crescente em algumas áreas. Vários estudos obtiveram êxito em correlacionar a má nutrição em estágios iniciais de vida com o desenvolvimento de doenças cardiovasculares e diabetes tipo 2 na vida adulta. No modelo de desnutrição pós desmame verifica-se menor secreção de insulina estimulada por glicose e outros agentes insulinotrópicos bem como menor expressão de várias proteínas envolvidas com a funcionalidade da célula b. Estudos realizados por nosso grupo e outros laboratórios mostram que a suplementação de camundongos com taurina aumenta a secreção de insulina além de regular o influxo de íons Ca2+ para as células b, etapa crucial para o processo secretório. Para avaliar os efeitos da taurina sobre animais desnutridos, utilizamos ratos wistar, machos com 21 dias de vida. Os animais receberam dieta contendo 17% de proteína (normoprotéica) (C) ou 6% de proteína (hipoprotéica) (D). Animais C e D receberam suplementação com taurina a 2,5% na água de beber por 30 dias (CT30 e DT30) ou 90 dias (CT90 e DT90). Em seguida avaliamos parâmetros biométricos e bioquímicos, tolerância à glicose, secreção de insulina estimulada por glicose e pelo agonista colinérgico carbacol, expressão de proteínas envolvidas no controle da secreção de insulina e, finalmente, registramos os movimentos citoplasmáticos de íons Ca2+ após estímulo com glicose e carbacol. Verificamos que a restrição protéica retardou o crescimento dos animais além de reduzir a concentração plasmática de proteínas totais (C = 6,81±0,04; CT30 = 7,15±0,54; CT90 = 6,87±0,19; D = 5,35±0,24; DT30 = 5,37±0,28; DT90 = 5,70±0,09 g/dl; n = 3-5) e albumina (C = 3,20±0,11; CT30 = 3,41±0,02; CT90 = 3,18±0,05; D = 2,74±0,07; DT30 = 2,49±0,09; DT90 = 2,67±0,04 g/dl; n = 5-9) sem efeito da suplementação com taurina. Os animais D se mostraram mais tolerantes à glicose e a suplementação com taurina por 90 dias restaurou parcialmente a tolerância desses animais (C = 30249±2682; CT30 = 37255±6691; CT90 = 29365±2257; D = 16916±1609; DT30 = 18791±2859; DT90 = 23425±3856 AAC; n = 5-9). Nesse trabalho mostramos que a suplementação com taurina corrige a hipoinsulinemia verificada em animais desnutridos alimentados (C = 4,97±0,34; CT90 = 3,56±0,52; D = 1,39±0,10; DT90 = 3,31±0,70 ng/ml; n = 5-8) bem como a responsividade de ilhotas isoladas a concentrações crescentes de glicose. Verificamos também que a taurina normaliza a secreção de insulina potencializada pelo carbacol (C = 9,4+0,8; CT90 = 12,4+0,7; D = 6,4+0,5; DT90 = 9+0,7 ng/ml; n = 12). As respostas secretórias foram observadas em conjunto com a regulação da expressão das proteínas SERCA3 (C = 100+21; CT90 = 174+17; D =96+90; DT90 = 149+11 % do C; n = 6), receptor muscarínico M3 (C = 100+24; CT90 = 155+80; D = 51+10; DT90 = 108+14 % do C; n = 5) e sintaxina 1 (C = 100+30; CT90 = 92+40; D = 50+12; DT90 = 77+11 % do C; n = 5) que participam do controle de diferentes etapas do processo de secreção de insulina. Por fim, verificamos que a suplementação com taurina melhorou o padrão de oscilação de íons Ca2+ após estímulo com glicose. Concluímos então que a suplementação com taurina por 90 dias restaura a sensibilidade das ilhotas à glicose e ao carbacol possivelmente pela regulação do fluxo de cálcio para as células b bem como pela modulação da expressão de proteínas que controlam o processo de secreção de insulina. Abstract: Malnutrition still is a public health issue, especially in developing countries. Many studies correlate malnourishment during early life and the development of cardiovascular disease and type 2 Diabetes Mellitus on latter stages. Animal models of malnutrition reveal impaired insulin secretion stimulated by glucose and other insulinotropic agents as well as lower expression of key proteins for b cell function. The literature shows that taurine supplementation increases insulin secretion and regulates calcium dynamics on b cells. Male, 21 days old, wistar rats received diet containing 17% (C) or 6% (D) of protein. Both groups received taurine supplementation on the drinking water for 30 (CT 30 and DT 30) and 90 (CT90 and DT 30) days. Next we assessed biometric and biochemical parameters, glucose tolerance, glucose and carbacholstimulated insulin secretion, protein expression of muscarinic M3 receptor, Phospholipase C b2, SERCA3, Syntaxin 1 and, finally, we registered cytoplasmic Ca2+ after stimulus with glucose and carbachol. Protein restricted rats showed lower body weight, plasma proteins (C = 6,81±0,04; CT30 = 7,15±0,54; CT90 = 6,87±0,19; D = 5,35±0,24; DT30 = 5,37±0,28; DT90 = 5,70±0,09 g/dl; n = 3-5), albumin (C = 3,20±0,11; CT30 = 3,41±0,02; CT90 = 3,18±0,05; D = 2,74±0,07; DT30 = 2,49±0,09; DT90 = 2,67±0,04 g/dl; n = 5-9) and increased glucose tolerance (C = 30249±2682; CT30 = 37255±6691; CT90 = 29365±2257; D = 16916±1609; DT30 = 18791±2859; DT90 = 23425±3856 AUC; n = 5-9). Taurine supplementation had no effect upon nutritional status parameters and partially restored glucose tolerance and insulinemia to C levels. Taurine increased secretory response to glucose and carbachol (C = 9,4+0,8; CT90 = 12,4+0,7; D = 6,4+0,5; DT90 = 9+0,7 ng/ml; n = 12). It also increased protein expression of M3 receptor (C = 100+24; CT90 = 155+80; D = 51+10; DT90 = 108+14 % of C; n = 5), SERCA 3 (C = 100+21; CT90 = 174+17; D =96+90; DT90 = 149+11 % of C; n = 6) and syntaxin 1 (C = 100+30; CT90 = 92+40; D = 50+12; DT90 = 77+11 % of C; n = 5). Finally, taurine supplementation for 90 days improved Ca2+ dynamics when the islets were stimulated with glucose. In conclusion, these data show that taurine supplementation restores secretory responsiveness to glucose and carbachol possibly through Ca2+ dynamics modulation and increased expression of key proteins for insulin secretion. Mestrado Fisiologia Mestre em Biologia Funcional e Molecular

A nefropatia diabética (ND) acomete até 40% dos pacientes com diabetes melito (DM) tipo 1 e tipo 2, sendo a principal causa de insuficiênca renal crônica naqueles pacientes que ingressam em programa de tratamento de substituição renal. A dieta parece ter um papel importante no desenvolvimento da doença. Existem evidências de que não apenas a quantidade mas o tipo de proteína ingerida também está associado à ND. Poucos estudos analisaram o papel dos lipídeos da dieta na ND. Dietas hipoprotéicas têm sido úteis em modificar de forma favorável a evolução da ND, desacelerando a perda de função renal em pacientes DM tipo 1 e ND. Existem poucos estudos em pacientes com DM tipo 2, porém estudos a curto prazo sugerem que esta dieta reduz a albuminúria. Entretanto, o seu uso a longo prazo é comprometido pela dificuldade de aderência à restrição protéica e pela sua segurança nutricional não estar ainda estabelecida. Resultados promissores são observados quando comparadas diferentes fontes de ingestão de proteína animal sobre a função renal e perfil lipídico sérico de pacientes com ND, podendo estas intervenções representar uma alternativa à dieta hipoprotéica no manejo dietoterápico nestes pacientes, ao atuar sobre os fatores de risco cardiovasculares e na função endotelial. Diabetic nephropathy (DN) is the leading cause of kidney disease in patients starting renal replacement therapy, and affects up to 40% of type 1 and type 2 diabetic patients. Diet seems to play an important role in the development of the disease. There are evidences supporting the concept that not only the amount but also the origin of dietary protein are associated with DN. Few studies analyzed the role of dietary lipids. A low-protein diet slows down the decline of renal function and ameliorates the DN prognosis and death in patients with type 1 diabetes with micro- and macroalbuminuria. Studies in type 2 diabetic patients are scanty but short-term studies suggest that this approach decreases albuminuria. However, the use of low-protein diet for long periods is compromised by poor compliance and its long-term safety is not firmly established. Enthusiastic results come up when comparing the effect of different sources of animal protein on renal function and lipid profile in patients with DN, which may represent an alternative strategy for low-protein diet on medical nutritional therapy in patients with DN and in cardiovascular risk factors and endothelial function.

It has been well documented that different therapeutic strategies, including angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs, and dietary protein restriction, lower urinary protein excretion in patients with diabetic and non-diabetic nephropathy. Experimental evidence suggests that this antiproteinuric effect is, at least in part, related to a reduction in the glomerular capillary hydraulic pressure. ACE inhibitors appear to achieve this reduction in glomerular capillary pressure, mainly through a fall in postglomerular arteriolar resistance, whereas dietary protein restriction and non-steroidal antiinflammatory drugs appear to invoke the response predominantly through an increase in preglomerular resistance. This leads to the suggestion that both ''glomerular preload reduction'' (afferent vasoconstriction) and ''glomerular afterload reduction'' (efferent vasodilation) will result in an antiproteinuric response. Interestingly, these same therapeutic regimens, particularly the ACE inhibitors and low-protein diets, have been proven to prevent progressive glomerulosclerosis in animal models. This concept of influencing glomerular hemodynamics both at the afferent and efferent arteriolar level may open new perspectives in the treatment of patients with renal protein loss and renal failure. At present, however, it is too early to conclude whether the fall in proteinuria induced by these treatments will also contribute to a better renal survival of these patients.