No description available.

Dietary factors may affect development and progression of prostate cancer. Experimental and epidemiological studies have suggested an effect of phytoestrogens on prostate cancer. Lignans are the predominant phytoestrogen in a Western diet. The effects of a diet rich in phytoestrogens and in particular lignans, as compared to a control diet, were assessed in several prostate cancer models. In paper I, 70 athymic nude mice with transplanted subcutaneous LNCaP tumours, an androgen sensitive human prostate cancer cell line, were fed one out of six phytoestrogen rich diets or a control diet after tumour injection. The rye diet, with high lignan content, decreased tumour take and growth, decreased secretion of prostate specific antigen and increased apoptosis. Addition of fat to the rye diet decreased the beneficial effects. In paper II, transgenic mice designed to develop prostate cancer (TRAMP) were fed rye bran or a control diet from the age of four weeks. Rye bran decreased prostate epithelial cell volume by 20%, and increased cell apoptosis by 31% as compared to the control diet. In paper III, we examined the effects of 7-hydroxymatairesinol (HMR), a purified lignan, in nude mice with subcutaneous LNCaP tumours in two different concentrations as compared to a control diet. Mice on the HMR diets had a reduced tumour take rate, lower total tumour volume, increased proportion of non-growing tumours, and increased apoptosis as compared to the control diet. Paper IV was a three week intervention study exploring the effects of rye bran bread vs. a control diet in men with prostate cancer. The men in the rye group had increased levels of plasma enterolactone and in biopsies from the prostate after the intervention an increase in apoptosis was observed in comparison with biopsies obtained before the intervention. In paper V, we examined the association between plasma levels of enterolactone, and risk of prostate cancer in a nested case control study. In the Northern Sweden Health and Disease Cohort, enterolactone concentrations were measured in plasma obtained at a mean time of 5 years before diagnosis from 265 cases of prostate cancer, and from 525 matched controls. We found no significant association between plasma enterolactone and risk of prostate cancer. Men with very low enterolactone levels (bottom decile) however, had significantly higher risk of prostate cancer. Phytoestrogen rich diet including soy, rye bran, substances purified from rye, and a purified lignan (HMR) all inhibited prostate tumour growth. However, it cannot be concluded that the effects observed were due solely to lignans as other components in rye grain such as tannins, phytic acid, ferulic acid, vitamins and minerals may have contributed to the beneficial effects. Thus, additional studies are needed to further elucidate the effects of phytoestrogens on prostate cancer development and progression.

O processo inflamatório subclinico encontra-se associado à prevenção e controle de um agrupamento de fatores de risco (FR) nutricionais, entre eles, dislipidemia e aumento de depósito de gordura visceral. Indicadores nutricionais, inflamatórios e metabólicos parecem estar associados com o estilo de vida. A semente de linhaça tem sido reconhecida como um alimento rico em fibras e -3, entretanto, um novo constituinte de sua composição nutricional tem merecido atenção, pelo seu papel antiinflamatório e antioxidante. Este componente é chamado de lignanas, um polímero complexo e o principal constituinte não-carbohidrato de plantas vasculares. Está ligado a fibras de celulose, e é responsável por reforçar a estrutura das paredes celulares, o que previne o colapso das mesmas. Lignanas, em contato com a microflora intestinal humana transformam-se em enterolignanas, especialmente, enterodiol e enterolactona. O presente trabalho tem por hipótese que o teor de lignanas dietético pode interferir no perfil metabólico, e alterar fatores de riscos envolvidos no estado nutricional, e consequentemente na saúde. O conhecimento de que diferentes características na composição nutricional de macronutrientes da dieta poderiam modificar o perfil inflamatório, independentemente, da presença das enterolignanas provenientes da semente de linhaça também constituíram o objetivo deste estudo. Por 42 dias, foram avaliados 52 funcionários, pertencentes ao sexo masculino, com idade média de 37± 9 anos, de uma indústria de grande porte, na cidade de Itu-SP. Os voluntários foram divididos em 4 grupos de pesquisa, sendo, um grupo controle, e três grupos com dietas isocalóricas e diferentes proporções no % de carboidratos (CH), e acréscimo de semente de linhaça em pó ou arroz cru triturados (protocolo duplo cego). Foi preenchida ficha de coleta de informações sobre dados pessoais e conhecimento de fatores de risco (hipertensão, dislipidemia e diabetes), comportamentos de risco (tabagismo e sedentarismo) e antecedentes familiares. Foi também realizada avaliação clinico - laboratorial, no qual se obteve o registro de medidas antropométricas, medida da pressão arterial e coleta de sangue venoso em jejum de 12 h para avaliação de indicadores bioquímicos referentes à FR cardiovascular, tais como, colesterol total e frações (LDL-c e HDL-c), triglicérides, glicemia, insulina, Homa-beta e Homa-IR, ácido úrico, bem como, para avaliação de indicadores inflamatórios (Proteína C Reativa (PCR), Fator de Necrose Tumoral (TNF-) e Isoprostane Sérico), hormonais (Leptina e Adiponectina) e nutricionais (Enterodiol e Enterolactona séricas e urinárias). Observou-se que para redução significativa das medidas antropométricas estudadas e indicador de estresse oxidativo não houve diferenças entre os grupos que receberam intervenção dietética. Entretanto, para a melhora do perfil bioquímico, inflamatório, hormonal e nutricional, diferentes respostas foram encontradas. Os grupos que receberam dietas com redução de CH total (32% e 35%) mostraram benefícios, no que se refere ao perfil bioquímico, especialmente, colesterol total, LDL-c e ácido úrico, como também, para o perfil hormonal, referente aos níveis de adiponectina (p <0,05). Com relação aos níveis de PCR e TNF-, apenas os grupos que tiveram acréscimo de semente de linhaça na dieta apresentaram redução significativa (p<0,05). Para os níveis de triglicérides, somente o grupo com adição de semente de linhaça e 32 % de CH total apresentou diminuição significativa (p<0,05). Foi observado que com 32 % de CH total ingerido e adição de um alimento rico em lignanas constituiu-se uma estratégia nutricional relevante, para prevenção primária de fatores de risco metabólicos e controle da inflamação subclinica, o que pode contribuir na redução da morbi-mortalidade a eles associada. / The control of subclinical inflammatory process is associated with the prevention nutritional RF (risk factor), such as dislipidemia and the increase of visceral fat deposition. Nutritional, inflammatory and metabolic indicators seem also to related to life style. The linseed has been recognized as rich in fibers and -3. However, a new component in its nutritional composition has deserved the attention for its anti- inflammatory and antioxidant roles. This component is called lignans, a complex polymer and the main non-carbohydrate constituent of vascular plants. It is binded to cellulose fibers and is responsible for reinforcing cell walls structure, preventing them from collapsing. Plant lignans, in contact with the human intestinal flora, become enterolignans, specially enterodiol and enterolactone. This present work hypothetically that the amount of dietetic plant lignans interfere in the metabolic profile, altering the risk factors involved in the nutritional health state and consequently, the welfare state. Therefore, the objective of this study is to know if different diet nutritional composition characteristics can change the inflammatory profile, independently of the presence of enterolignans from the linseed. For 42 days, 52 male volunteers, average 37±9 years old, from a industrial city of Itu-SP, were evaluated. The volunteers were divided into 4 research groups; one control group and 3 groups on isocaloric diets with different proportion of carbohydrate (CH) and the addition of powdered linseed or ground raw rice (a double blind protocol). Personal data, RF (hypertension, dislipidemia and diabetes), habits (smoking and sedentary) and family antecedents were collected. A nutritional-laboratorial evaluation was performed in order to get anthropometric data; blood pressure checked and blood samples (after 12 hours fast) for total cholesterol and fractions (LDL-c and HDL-c ), triglycerides, glycemia, insulin, Homa-beta and Homa-IR, uric acid, inflammatory indicators (Reactive-C Protein (PCR) , Tumoral Necrosis Factor (TNF-a) and Seric Isoprostane ), hormonal (Leptin and Adiponectin), enterodiol and enterolactone seric and urinary enterolignins. It was observed a reduction of the studied anthropometric measures and for the oxidative stress indicators. A significant change occurred in the anthropometric measurements and the oxidative stress marker evaluated for all groups, but no difference among them was noted. On the other hand, biochemical, inflammatory, hormonal and nutritional profile significant differences among groups was observed. The groups that received diets with the reduction of the total CH (32% and 35% ) showed improvements in the biochemical profile, specially in the total cholesterol, LDL-c and uric acid, as well as the hormonal profile, in the levels of adiponectin (p< 0,05) . The levels of PCR and TNF-a, only the groups that had the linseed, showed a reduction (p< 0,05). For the triglycerides levels, only the group with the addition of linseed and 32% of total CH showed a decrease. It was observed with 32% of CH and the addition of food lignans constitute a nutritional relevant strategy for the primary prevention of metabolic risk factors and control of subclinical inflammation, contributing to the reduction of the associated morbi-mortality.

The rising use of natural products creates an imperative need for an enhanced awareness of the safety of current and new products making their way into the marketplace. An important example is natural products containing lignans as the principal active component. Despite their structural similarity the lignan of creosote bush can cause hepato- and renal toxicity while the lignans of flaxseed have no reported serious toxicity. This dissertation aimed to investigate the oxidative metabolism of such lignans to determine whether reversible, competitive interactions and/or bioactivation may explain the differences in their apparent toxicity.<p> The first objective was to study the metabolism and bioactivation of nordihydroguaiaretic acid (creosote bush) and secoisolariciresinol (flaxseed). Nordihydroguaiaretic acid metabolism in rat liver microsomes led to the production of three glutathione adducts formed via ortho¬-quinone reactive intermediates. This metabolism was independent of NADPH and thus attributed to autoxidation. Secoisolariciresinol metabolism yielded lariciresinol and no glutathione adducts suggesting an absence of bioactivation to reactive quinone intermediates.<p> The second objective was to study the autoxidation of nordihydroguaiaretic acid. The major autoxidation product was a unique, stable schisandrin-like cyclolignan which was the result of nordihydroguaiaretic acid cyclization. The half-life of nordihydroguaiaretic acid in aqueous solution, pH 7.4, 37ºC is 3.14 hours suggesting the cyclolignan may be responsible for some of the biological effects of nordihydroguaiaretic acid.<p> The third objective was to study the inhibition of cytochrome P450 isoforms 1A2, 2B, 2C11 and 3A by lignans derived from creosote bush and flaxseed. None of the lignans caused irreversible inhibition. Both creosote bush and flaxseed lignans caused reversible inhibition of P450 enzyme activity that involved competitive or mixed-type inhibition, however the inhibition was present at nonphysiologically relevant concentrations. Activation of cytochrome P450 isoforms was also observed at low lignan concentrations. The results suggest that P450-mediated bioactivation or reversible inhibition cannot explain the differences in toxicity noted between the lignans of creosote bush and flaxseed.<p> This work suggests a minimal risk for drug-lignan interactions at P450 enzymes. Further studies are warranted to determine the presence and biological and toxicological role of the nordihydroguaiaretic acid cyclolignan in herbal preparations.

The rising use of natural products creates an imperative need for an enhanced awareness of the safety of current and new products making their way into the marketplace. An important example is natural products containing lignans as the principal active component. Despite their structural similarity the lignan of creosote bush can cause hepato- and renal toxicity while the lignans of flaxseed have no reported serious toxicity. This dissertation aimed to investigate the oxidative metabolism of such lignans to determine whether reversible, competitive interactions and/or bioactivation may explain the differences in their apparent toxicity.<p> The first objective was to study the metabolism and bioactivation of nordihydroguaiaretic acid (creosote bush) and secoisolariciresinol (flaxseed). Nordihydroguaiaretic acid metabolism in rat liver microsomes led to the production of three glutathione adducts formed via ortho¬-quinone reactive intermediates. This metabolism was independent of NADPH and thus attributed to autoxidation. Secoisolariciresinol metabolism yielded lariciresinol and no glutathione adducts suggesting an absence of bioactivation to reactive quinone intermediates.<p> The second objective was to study the autoxidation of nordihydroguaiaretic acid. The major autoxidation product was a unique, stable schisandrin-like cyclolignan which was the result of nordihydroguaiaretic acid cyclization. The half-life of nordihydroguaiaretic acid in aqueous solution, pH 7.4, 37ºC is 3.14 hours suggesting the cyclolignan may be responsible for some of the biological effects of nordihydroguaiaretic acid.<p> The third objective was to study the inhibition of cytochrome P450 isoforms 1A2, 2B, 2C11 and 3A by lignans derived from creosote bush and flaxseed. None of the lignans caused irreversible inhibition. Both creosote bush and flaxseed lignans caused reversible inhibition of P450 enzyme activity that involved competitive or mixed-type inhibition, however the inhibition was present at nonphysiologically relevant concentrations. Activation of cytochrome P450 isoforms was also observed at low lignan concentrations. The results suggest that P450-mediated bioactivation or reversible inhibition cannot explain the differences in toxicity noted between the lignans of creosote bush and flaxseed.<p> This work suggests a minimal risk for drug-lignan interactions at P450 enzymes. Further studies are warranted to determine the presence and biological and toxicological role of the nordihydroguaiaretic acid cyclolignan in herbal preparations.

O processo inflamatório subclinico encontra-se associado à prevenção e controle de um agrupamento de fatores de risco (FR) nutricionais, entre eles, dislipidemia e aumento de depósito de gordura visceral. Indicadores nutricionais, inflamatórios e metabólicos parecem estar associados com o estilo de vida. A semente de linhaça tem sido reconhecida como um alimento rico em fibras e -3, entretanto, um novo constituinte de sua composição nutricional tem merecido atenção, pelo seu papel antiinflamatório e antioxidante. Este componente é chamado de lignanas, um polímero complexo e o principal constituinte não-carbohidrato de plantas vasculares. Está ligado a fibras de celulose, e é responsável por reforçar a estrutura das paredes celulares, o que previne o colapso das mesmas. Lignanas, em contato com a microflora intestinal humana transformam-se em enterolignanas, especialmente, enterodiol e enterolactona. O presente trabalho tem por hipótese que o teor de lignanas dietético pode interferir no perfil metabólico, e alterar fatores de riscos envolvidos no estado nutricional, e consequentemente na saúde. O conhecimento de que diferentes características na composição nutricional de macronutrientes da dieta poderiam modificar o perfil inflamatório, independentemente, da presença das enterolignanas provenientes da semente de linhaça também constituíram o objetivo deste estudo. Por 42 dias, foram avaliados 52 funcionários, pertencentes ao sexo masculino, com idade média de 37± 9 anos, de uma indústria de grande porte, na cidade de Itu-SP. Os voluntários foram divididos em 4 grupos de pesquisa, sendo, um grupo controle, e três grupos com dietas isocalóricas e diferentes proporções no % de carboidratos (CH), e acréscimo de semente de linhaça em pó ou arroz cru triturados (protocolo duplo cego). Foi preenchida ficha de coleta de informações sobre dados pessoais e conhecimento de fatores de risco (hipertensão, dislipidemia e diabetes), comportamentos de risco (tabagismo e sedentarismo) e antecedentes familiares. Foi também realizada avaliação clinico - laboratorial, no qual se obteve o registro de medidas antropométricas, medida da pressão arterial e coleta de sangue venoso em jejum de 12 h para avaliação de indicadores bioquímicos referentes à FR cardiovascular, tais como, colesterol total e frações (LDL-c e HDL-c), triglicérides, glicemia, insulina, Homa-beta e Homa-IR, ácido úrico, bem como, para avaliação de indicadores inflamatórios (Proteína C Reativa (PCR), Fator de Necrose Tumoral (TNF-) e Isoprostane Sérico), hormonais (Leptina e Adiponectina) e nutricionais (Enterodiol e Enterolactona séricas e urinárias). Observou-se que para redução significativa das medidas antropométricas estudadas e indicador de estresse oxidativo não houve diferenças entre os grupos que receberam intervenção dietética. Entretanto, para a melhora do perfil bioquímico, inflamatório, hormonal e nutricional, diferentes respostas foram encontradas. Os grupos que receberam dietas com redução de CH total (32% e 35%) mostraram benefícios, no que se refere ao perfil bioquímico, especialmente, colesterol total, LDL-c e ácido úrico, como também, para o perfil hormonal, referente aos níveis de adiponectina (p <0,05). Com relação aos níveis de PCR e TNF-, apenas os grupos que tiveram acréscimo de semente de linhaça na dieta apresentaram redução significativa (p<0,05). Para os níveis de triglicérides, somente o grupo com adição de semente de linhaça e 32 % de CH total apresentou diminuição significativa (p<0,05). Foi observado que com 32 % de CH total ingerido e adição de um alimento rico em lignanas constituiu-se uma estratégia nutricional relevante, para prevenção primária de fatores de risco metabólicos e controle da inflamação subclinica, o que pode contribuir na redução da morbi-mortalidade a eles associada. / The control of subclinical inflammatory process is associated with the prevention nutritional RF (risk factor), such as dislipidemia and the increase of visceral fat deposition. Nutritional, inflammatory and metabolic indicators seem also to related to life style. The linseed has been recognized as rich in fibers and -3. However, a new component in its nutritional composition has deserved the attention for its anti- inflammatory and antioxidant roles. This component is called lignans, a complex polymer and the main non-carbohydrate constituent of vascular plants. It is binded to cellulose fibers and is responsible for reinforcing cell walls structure, preventing them from collapsing. Plant lignans, in contact with the human intestinal flora, become enterolignans, specially enterodiol and enterolactone. This present work hypothetically that the amount of dietetic plant lignans interfere in the metabolic profile, altering the risk factors involved in the nutritional health state and consequently, the welfare state. Therefore, the objective of this study is to know if different diet nutritional composition characteristics can change the inflammatory profile, independently of the presence of enterolignans from the linseed. For 42 days, 52 male volunteers, average 37±9 years old, from a industrial city of Itu-SP, were evaluated. The volunteers were divided into 4 research groups; one control group and 3 groups on isocaloric diets with different proportion of carbohydrate (CH) and the addition of powdered linseed or ground raw rice (a double blind protocol). Personal data, RF (hypertension, dislipidemia and diabetes), habits (smoking and sedentary) and family antecedents were collected. A nutritional-laboratorial evaluation was performed in order to get anthropometric data; blood pressure checked and blood samples (after 12 hours fast) for total cholesterol and fractions (LDL-c and HDL-c ), triglycerides, glycemia, insulin, Homa-beta and Homa-IR, uric acid, inflammatory indicators (Reactive-C Protein (PCR) , Tumoral Necrosis Factor (TNF-a) and Seric Isoprostane ), hormonal (Leptin and Adiponectin), enterodiol and enterolactone seric and urinary enterolignins. It was observed a reduction of the studied anthropometric measures and for the oxidative stress indicators. A significant change occurred in the anthropometric measurements and the oxidative stress marker evaluated for all groups, but no difference among them was noted. On the other hand, biochemical, inflammatory, hormonal and nutritional profile significant differences among groups was observed. The groups that received diets with the reduction of the total CH (32% and 35% ) showed improvements in the biochemical profile, specially in the total cholesterol, LDL-c and uric acid, as well as the hormonal profile, in the levels of adiponectin (p< 0,05) . The levels of PCR and TNF-a, only the groups that had the linseed, showed a reduction (p< 0,05). For the triglycerides levels, only the group with the addition of linseed and 32% of total CH showed a decrease. It was observed with 32% of CH and the addition of food lignans constitute a nutritional relevant strategy for the primary prevention of metabolic risk factors and control of subclinical inflammation, contributing to the reduction of the associated morbi-mortality.

Cardiovascular diseases are the leading cause of death in most industrialised countries and in developing countries the trend in cardiovascular-related deaths is increasing. World-wide, type 2 diabetes mellitus (T2DM) is an emerging cause of disability and premature death. Both these conditions are closely associated with the consumption of energy-dense foods and food products that are poor in nutrients, as well as with a sedentary lifestyle. Pharmacological and surgical interventions can improve the outcome and delay the progression of the disease, but in terms of population-level prevention there is no substitute for the adoption of a healthy lifestyle. SETTING The underlying studies were conducted in Västerbotten (the VIP study), and in Norrbotten and Västerbotten combined (the MONICA Project). Norrbotten andVästerbotten are the two northernmost counties in Sweden. Since the mid-1980sthe prevalence of cardiovascular disease has decreased and diabetes rates haveremained stable in this region, despite of an unbroken trend of increasing body weight. OBJECTIVE The aim of this thesis is to describe changes in reported dietary habits, estimatetheir relative importance as risk factors for diabetes and cardiovascular disease, and finally to identify lifestyle components as potential targets for intervention. RESULTS The first paper describes changes in self-reported food consumption between 1986 and 1999. During this period, the population in question switched from products with high saturated fatty acid content (e.g. milk containing 3% fat, butter) to foods containing less saturated fat (e.g. milk containing 1.5% fat, vegetable oil, low-fat margarine); pasta and rice were consumed more often, and potatoes were consumed less. Convenience foods (e.g. hamburgers, snacks, sweets) became more popular, whilst traditional dishes (e.g. potato dumplings, black pudding, blöta) decreased in popularity. Fruit and vegetable intake remained low. In paper two we study the effects of these changes in food intake on the risk of developing T2DM using body fat distribution as an early indicator. Increased consumption of convenience foods was associated with unfavourable changes (smaller hip circumference and larger waist circumference), whereas the increased consumption of vegetable oil and pasta was associated with low-risk fat distribution. In the third paper we report studies on the association between fat consumption and T2DM. We used the pattern of fatty acids in the membranes of red blood cells as a marker of fat intake. In addition to confirming earlier findings (markers of the intake of saturated fat are associated with increased risk of T2DM and markers of unsaturated fat are associated with reduced T2DM risk), we also identified associations between two markers of milk-derived saturated fat intake and enterolactone, a biomarker of dietary fibre intake, and the risk of developing myocardial infarction. Our results indicate that moderately high levels of enterolactone intake in men are associated with lower risk of experiencing myocardial infarction. Manuscript 5 ranks education level, physical activity, smoking status, and self-reported intake of dietary fibre and fatty acids according to their effects on body fat distribution. Increased levels of physical activity, a higher education level and a reduced intake of saturated fat from meat were ranked as the most strongly associated factors in both men and women. Increased intake of dietary fibre from grains in women, and increased intake of dietary fibre from fruits and vegetables in men, was also inversely associated with average waist circumference. CONCLUSION Both questionnaire-based and biological markers of the risk of developing diabetes or cardiovascular disease have been identified. Based on available population level measurements, reduced consumption of convenience foods, increased consumption of whole-grain products, fruits and vegetables, vegetable oil and pasta as well as increased physical activity are potential goals for interventions in northern Sweden.