Oral consumption of flaxseed improves serum lipid parameters, and the flaxseed lignan, secoisolariciresinol diglucoside (SDG) may mediate these effects. SDGs therapeutic potential cannot be fully realized until its mechanism of action and pharmacokinetics are more completely characterized.</p>This research aimed to assess SDGs effects in dietary models of hypertriglyceridemia, hypercholesterolemia, and obesity. Furthermore, this thesis work provided preliminary pharmacokinetic data on SDGs aglycone form, secoisolariciresinol (SECO). Dietary manipulations were used to induce hyperlipidemic states in female Wistar or male Sprague-Dawley rats. Groups of 10 rats were randomly assigned to one of three (obesity and cholesterol diets) or four (fructose) treatment groups: 1) Normal diet with 0.0 µmol SDG/kg body weight; 2) Dietary manipulation with 0.0 µmol SDG/kg; 3) Dietary manipulation with 4.4 µmol SDG/kg; and 4) 10% fructose in water with 8.8 µmol SDG/kg. Lignan or vehicle (saline) was administered daily by oral gavage for four weeks (2 weeks for male Sprague-Dawleys). After four (or two) weeks of SDG administration, body and liver weights were recorded, serum lipids were measured using enzymatic kits, hepatic fat accumulation was determined by histochemical analysis and hepatic mRNA expression of triglyceride pathway targets was evaluated using real-time RT-PCR. A 10% fructose in water model was effective for the induction of hypertriglyceridemia in male Sprague-Dawley rats but ineffective in female Wistar rats of similar age. Neither 4.4 nor 8.8 µmol SDG/kg improved serum and hepatic triglyceride parameters in male Sprague-Dawley rats on a 10% fructose in water diet. It is suspected that gender and strain are important factors for this model of hypertriglyceridemia. Dietary manipulations for the induction of hypercholesterolemia and obesity in female Wistar rats were not effective following 4 weeks administration of a 1% cholesterol diet and a 45% fat diet respectively. Since previous studies were able to successfully induce hypercholesterolemia in the same model, it is suspected that the differences in age of the animals accounted for the inconsistent results. Strain, gender and age of animals were identified as important considerations when trying to induce hyperlipidemic states through dietary manipulations.</p>SDG (4.4 µmol/kg) dosed daily for four weeks caused no gross morphological organ changes or alterations in blood chemistry or hematology parameters. Following an intravenous bolus (10 mg/kg), secoisolariciresinol (SECO) disposition was consistent with two-compartment pharmacokinetics, with distribution and elimination half-lives at 26 seconds and 5 minutes, respectively. No SECO was detected in the plasma following an oral bolus (10 mg/kg). Further investigation into SDGs hypolipidemic effects are required to elucidate its mechanism of action. A complete pharmacokinetic study is warranted to fully understand SDGs safety and efficacy.

Oral consumption of flaxseed improves serum lipid parameters, and the flaxseed lignan, secoisolariciresinol diglucoside (SDG) may mediate these effects. SDGs therapeutic potential cannot be fully realized until its mechanism of action and pharmacokinetics are more completely characterized.</p>This research aimed to assess SDGs effects in dietary models of hypertriglyceridemia, hypercholesterolemia, and obesity. Furthermore, this thesis work provided preliminary pharmacokinetic data on SDGs aglycone form, secoisolariciresinol (SECO). Dietary manipulations were used to induce hyperlipidemic states in female Wistar or male Sprague-Dawley rats. Groups of 10 rats were randomly assigned to one of three (obesity and cholesterol diets) or four (fructose) treatment groups: 1) Normal diet with 0.0 µmol SDG/kg body weight; 2) Dietary manipulation with 0.0 µmol SDG/kg; 3) Dietary manipulation with 4.4 µmol SDG/kg; and 4) 10% fructose in water with 8.8 µmol SDG/kg. Lignan or vehicle (saline) was administered daily by oral gavage for four weeks (2 weeks for male Sprague-Dawleys). After four (or two) weeks of SDG administration, body and liver weights were recorded, serum lipids were measured using enzymatic kits, hepatic fat accumulation was determined by histochemical analysis and hepatic mRNA expression of triglyceride pathway targets was evaluated using real-time RT-PCR. A 10% fructose in water model was effective for the induction of hypertriglyceridemia in male Sprague-Dawley rats but ineffective in female Wistar rats of similar age. Neither 4.4 nor 8.8 µmol SDG/kg improved serum and hepatic triglyceride parameters in male Sprague-Dawley rats on a 10% fructose in water diet. It is suspected that gender and strain are important factors for this model of hypertriglyceridemia. Dietary manipulations for the induction of hypercholesterolemia and obesity in female Wistar rats were not effective following 4 weeks administration of a 1% cholesterol diet and a 45% fat diet respectively. Since previous studies were able to successfully induce hypercholesterolemia in the same model, it is suspected that the differences in age of the animals accounted for the inconsistent results. Strain, gender and age of animals were identified as important considerations when trying to induce hyperlipidemic states through dietary manipulations.</p>SDG (4.4 µmol/kg) dosed daily for four weeks caused no gross morphological organ changes or alterations in blood chemistry or hematology parameters. Following an intravenous bolus (10 mg/kg), secoisolariciresinol (SECO) disposition was consistent with two-compartment pharmacokinetics, with distribution and elimination half-lives at 26 seconds and 5 minutes, respectively. No SECO was detected in the plasma following an oral bolus (10 mg/kg). Further investigation into SDGs hypolipidemic effects are required to elucidate its mechanism of action. A complete pharmacokinetic study is warranted to fully understand SDGs safety and efficacy.

Secoisolariciresinol (SECO) is the major lignan present in flaxseed, but unlike the structurally related lignan nordihydroguaiaretic acid, it is not associated with toxicity. The major phase I metabolite of SECO is lariciresinol, likely formed as a result of para-quinone methide (p-QM) formation followed by an intramolecular cyclization, thereby minimizing any toxicity associated with the p-QM. Four analogues of SECO were used to investigate substituent effects on lignan metabolism and formation of reactive quinones. HPLC methods were developed for analysis of SECO analogues and their metabolites. The stability of SECO analogues (1 mM) in a 50 mM Na2HPO4 buffer at pH 6.0 and 7.4 were quantified. Enzymatic oxidation experiments using mushroom tyrosinase and microsomes harvested from male Sprague-Dawley rats were performed with and without a GSH trapping system. Mass spectrometry and LC-MS were used to identify metabolites. Life Technologies was contracted to perform IC50 inhibition assays on SECO and the SECO analogues against CYP3A4, CYP3A5, CYP2C9 and CYP2C19 cytochrome P450 isoforms. All SECO analogues were stable at pH 6.0. SECO-2 was stable at pH 7.4 but SECO-1, -3 and -4 were unstable at pH 7.4. Autoxidation of SECO -1, -3 and -4 were 1st order reactions with t1/2 of 9.0 h, 1.7 h and 7.0 h respectively. Mushroom tyrosinase oxidations were performed to generate ortho-quinone standards. SECO-1 -3 and -4 were oxidized by mushroom tyrosinase but SECO-2 was not. Trapping with GSH produces aromatic ring conjugates for SECO-1, -3, -4. Results from microsomal oxidations for SECO-1, -3 and -4 are consistent with these standards. SECO-2 was metabolized by a microsomal system to produce a benzyl GSH adduct. Dealkylation products were also observed. All SECO analogues formed quinones but interestingly, GSH conjugation was competitive with intramolecular cyclization. All cytochrome P450 isoforms were inhibited by every analogue tested to varying degrees, a potential cause of toxicity concerns. Quinones are known to cause toxicity in vivo, including cytotoxicity, immunotoxicity, and carcinogenesis. Our results suggest that since the phenol and catechol lignans form GSH adducts in addition to intramolecular cyclization products, this class of lignans have the potential to cause toxicity.

O presente trabalho teve como objetivo realizar a extração de lignanas e outros compostos fenólicos do farelo de linhaça desengordurado e avaliar a atividade antifúngica dessas frações frente a fungos leveduriformes do gênero Candida. Obteve-se o extrato bruto através de maceração com solução hidroalcólica. O extrato bruto foi hidrolisado em condições básicas e ácidas, objetivando-se o isolamento de heterosídeos e agliconas, respecitvamete. A lignana secoisolariciresinol diglicosídeo foi quantificada por cromatografia líquida de alta eficiência. O flavonoide herbacetin diglicosídeo e a lignana anidrosecoisolariciresinol foram identificados por espectrometria de massas. A avaliação da atividade antifúngica foi realizada in vitro e foi observado que tanto o extrato bruto como o extrato obtido por hidrólise alcalina inibiram o desenvolvimento de Candida krusei CK 02 e Candida parapsilosis RL 20 na concentração de 500 μg/mL. O extrato obtido por hidrólise ácida, na mesma concentração, apresentou atividade inibitória frente a Candida krusei CK 02, Candida parapsilosis RL 20 e Candida tropicallis ATCC 750. A investigação das condições de hidrólise ácida, a melhor caracterização de seus componentes e a avaliação da ação antifúngica dos extratos frente a outros gêneros de fungos constituem perspectivas para trabalhos futuros. / The aim of the present work was carry out the extraction of lignans and other phenolic compounds from defatted flaxseed meal and evaluate the antifungal activity of these fractions against yeast fungi of Candida genus. The crude extract was obtained by maceration with a hydroalcoholic solution. The crude extract was hydrolyzed in basic and acidic conditions, aiming the isolation of glycosides and aglycones, respectively. Secoisolariciresinol diglucoside was quantified by highperformance liquid chromatography. The flavonoid herbacetin diglucoside and the lignan anhydrosecoisolariciresinol were identified by mass spectrometry. The avaliation of antifungal activity was performed in vitro and it was observed that both the crude extract and the extract obtained by alkaline hydrolysis inhibited the development of Candida krusei CK 02 and Candida parapsilosis RL 20 at a concentration of 500 ug/mL. The extract obtained by acid hydrolysis, in the same concentration, showed inhibitory activity against Candida krusei CK 02, Candida parapsilosis RL 20 and Candida tropicallis ATCC 750. The investigation of acid hydrolysis conditions, a better characterization of its components and the avaliation of antifungal activity against other fungi genera represents good potencial for future work.

O presente trabalho teve como objetivo realizar a extração de lignanas e outros compostos fenólicos do farelo de linhaça desengordurado e avaliar a atividade antifúngica dessas frações frente a fungos leveduriformes do gênero Candida. Obteve-se o extrato bruto através de maceração com solução hidroalcólica. O extrato bruto foi hidrolisado em condições básicas e ácidas, objetivando-se o isolamento de heterosídeos e agliconas, respecitvamete. A lignana secoisolariciresinol diglicosídeo foi quantificada por cromatografia líquida de alta eficiência. O flavonoide herbacetin diglicosídeo e a lignana anidrosecoisolariciresinol foram identificados por espectrometria de massas. A avaliação da atividade antifúngica foi realizada in vitro e foi observado que tanto o extrato bruto como o extrato obtido por hidrólise alcalina inibiram o desenvolvimento de Candida krusei CK 02 e Candida parapsilosis RL 20 na concentração de 500 μg/mL. O extrato obtido por hidrólise ácida, na mesma concentração, apresentou atividade inibitória frente a Candida krusei CK 02, Candida parapsilosis RL 20 e Candida tropicallis ATCC 750. A investigação das condições de hidrólise ácida, a melhor caracterização de seus componentes e a avaliação da ação antifúngica dos extratos frente a outros gêneros de fungos constituem perspectivas para trabalhos futuros. / The aim of the present work was carry out the extraction of lignans and other phenolic compounds from defatted flaxseed meal and evaluate the antifungal activity of these fractions against yeast fungi of Candida genus. The crude extract was obtained by maceration with a hydroalcoholic solution. The crude extract was hydrolyzed in basic and acidic conditions, aiming the isolation of glycosides and aglycones, respectively. Secoisolariciresinol diglucoside was quantified by highperformance liquid chromatography. The flavonoid herbacetin diglucoside and the lignan anhydrosecoisolariciresinol were identified by mass spectrometry. The avaliation of antifungal activity was performed in vitro and it was observed that both the crude extract and the extract obtained by alkaline hydrolysis inhibited the development of Candida krusei CK 02 and Candida parapsilosis RL 20 at a concentration of 500 ug/mL. The extract obtained by acid hydrolysis, in the same concentration, showed inhibitory activity against Candida krusei CK 02, Candida parapsilosis RL 20 and Candida tropicallis ATCC 750. The investigation of acid hydrolysis conditions, a better characterization of its components and the avaliation of antifungal activity against other fungi genera represents good potencial for future work.

O presente trabalho teve como objetivo realizar a extração de lignanas e outros compostos fenólicos do farelo de linhaça desengordurado e avaliar a atividade antifúngica dessas frações frente a fungos leveduriformes do gênero Candida. Obteve-se o extrato bruto através de maceração com solução hidroalcólica. O extrato bruto foi hidrolisado em condições básicas e ácidas, objetivando-se o isolamento de heterosídeos e agliconas, respecitvamete. A lignana secoisolariciresinol diglicosídeo foi quantificada por cromatografia líquida de alta eficiência. O flavonoide herbacetin diglicosídeo e a lignana anidrosecoisolariciresinol foram identificados por espectrometria de massas. A avaliação da atividade antifúngica foi realizada in vitro e foi observado que tanto o extrato bruto como o extrato obtido por hidrólise alcalina inibiram o desenvolvimento de Candida krusei CK 02 e Candida parapsilosis RL 20 na concentração de 500 μg/mL. O extrato obtido por hidrólise ácida, na mesma concentração, apresentou atividade inibitória frente a Candida krusei CK 02, Candida parapsilosis RL 20 e Candida tropicallis ATCC 750. A investigação das condições de hidrólise ácida, a melhor caracterização de seus componentes e a avaliação da ação antifúngica dos extratos frente a outros gêneros de fungos constituem perspectivas para trabalhos futuros. / The aim of the present work was carry out the extraction of lignans and other phenolic compounds from defatted flaxseed meal and evaluate the antifungal activity of these fractions against yeast fungi of Candida genus. The crude extract was obtained by maceration with a hydroalcoholic solution. The crude extract was hydrolyzed in basic and acidic conditions, aiming the isolation of glycosides and aglycones, respectively. Secoisolariciresinol diglucoside was quantified by highperformance liquid chromatography. The flavonoid herbacetin diglucoside and the lignan anhydrosecoisolariciresinol were identified by mass spectrometry. The avaliation of antifungal activity was performed in vitro and it was observed that both the crude extract and the extract obtained by alkaline hydrolysis inhibited the development of Candida krusei CK 02 and Candida parapsilosis RL 20 at a concentration of 500 ug/mL. The extract obtained by acid hydrolysis, in the same concentration, showed inhibitory activity against Candida krusei CK 02, Candida parapsilosis RL 20 and Candida tropicallis ATCC 750. The investigation of acid hydrolysis conditions, a better characterization of its components and the avaliation of antifungal activity against other fungi genera represents good potencial for future work.

Les lignanes sont des métabolites secondaires végétaux, dont la fonction biologique reste aujourd’hui inconnue in planta, mais qui présentent un intérêt en santé humaine. Cette étude vise à progresser dans la connaissance de la fonction des lignanes dans la plante en étudiant la régulation de la biosynthèse de ces molécules. Cette étude a été menée chez des lins : Linum usitatissimum (espèce cultivée) et Linum flavum (espèce sauvage). Chez Linum usitatissimum, la régulation spatio-temporelle de la biosynthèse des lignanes a été établie et il a été démontré que l’acide abscissique régulait la biosynthèse des lignanes dans la graine. Chez Linum flavum, un gène clé dans la production de lignanes a été isolé et la régulation spatiotemporelle de la biosynthèse des lignanes a été établie. Un protocole amélioré d’extraction de sécoisolaricirésinol utilisant une cellulase a été mis au point à partir de téguments de graines de Linum usitatissimum. Enfin de nouvelles sources de lignanes cytotoxiques parmi les Juniperus et Callitris ont été identifiées, et l’extraction de ces composés à partir de feuilles a été optimisée. / Lignans are plant secondary metabolites whose in planta biological function is still unknown but are of interest for human health. This work aims at understanding the function of plant lignans through the study of the lignans biosynthesis regulation. This study was conducted in flax: Linum usitatissimum (cultivated species) and Linum flavum (wild species). In Linum usitatissimum, spatial and temporal regulation of lignans biosynthesis has been established and it has been shown that abscisic acid regulates the lignan biosynthesis in seed coats. In Linum flavum, a key gene of lignans production has been isolated, spatial and temporal regulation of lignans biosynthesis has been established. An improved protocol for secoisolariciresinol extraction from Linum usitatissimum seed teguments involving the use of a cellulase was developed. Finally new sources of cytotoxic lignans were identified among Juniperus and Callitris species and extraction from leaves was optimized.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Avaliamos o efeito do consumo materno de SDG (Diglicosídeo Secoisolariciresinol) e de óleo de Linhaça+SDG sobre parâmetros bioquímicos e hormonais das ratas e das proles machos e fêmeas na lactação. As ratas lactantes foram separadas em: controle (C), ração controle cuja proteína foi caseína; (SDG): ração C com 400mg de SDG/Kg de ração; OLSDG: ração C com 400mg de SDG/Kg de ração e 7% de óleo de linhaça. No 14 e 20 dias de lactação as ratas foram ordenhadas e no 21 dia foram sacrificadas por punção cardíaca. Leite e soro foram coletados para avaliação bioquímica e hormonal. Hormônios foram quantificados por radioimunoensaio. As proles machos e fêmeas foram sacrificadas aos 14 e 21 dias de idade. Os animais foram eviscerados para análise da composição corporal. Monitoramos a ingestão alimentar e a massa corporal (MC) durante o período experimental. As ratas SDG apresentaram maior gordura corporal (GC; +39%), enquanto as OLSDG menor conteúdo mineral (-20%) e trigliceridemia (TG) (-39%). As ratas SDG e OLSDG apresentaram hiperprolactinemia (+389% e 153%, respectivamente) sem alteração na concentração de estradiol. No 14 dia de lactação, o leite das ratas OLSDG apresentou menores teores de lactose(-17%) e de proteínas (-20%) e o das ratas SDG apenas menor teor de proteína (-21%). A partir do 13 dia de lactação tanto os machos quanto as fêmeas OLSDG apresentaram menor MC (-14%, -16%, respectivamente). No 14 dia de lactação os machos SDG e OLSDG apresentaram menor gordura corporal (-24%, -55%, respectivamente ) e a prole SDG maior massa de gordura visceral (+39%). Os machos SDG apresentaram maiores concentrações de TG (+105%) e hipoprolactinemia (-41%). Os machos OLSDG também apresentaram hipoprolactinemia (-41%). As fêmeas SDG e OLSDG apresentaram maior estradiol aos 14 dias (+86% e +176%) que se normalizou aos 21 dias, maior colesterolemia (+16%) e as SDG apresentaram maior trigliceridemia (+74%). Aos 21 dias os machos e as fêmeas SDG e OLSDG apresentaram menor trigliceridemia (-48%, -54%,42% e -59%, respectivamente). Os dois componentes principais da semente de linhaça produzem alterações bioquímicas e hormonais tanto nas mães, quanto nas proles, independente do sexo. Entretanto, as alterações observadas diferem entre mães e prole e de acordo com o gênero. Entre as alterações mais importantes ressaltamos a hiperprolactinemia materna que pode ser um dos motivos para a hipoprolactinemia da prole e a hipertrigliceridemia causada pela ingestão de SDG pelas mães. / We evaluated the mothers intake of SDG (Diglicoside secoisolariciresinol) and flaxseed oil + SDG upon biochemical and hormonal parameters of lactating female rats and the male and female offspring during lactation. The female lactating rats were divided into: Control (C): feeding a diet with casein; (SDG): feeding diet C added 400mg of SDG/Kg diet; (OLSDG): diet C added 400mg of SDG/Kg diet and 7% of flaxseed oil. Milk samples were obtained on the 14th and 20th days of lactation and the mothers were sacrificed and blood collected by cardiac puncture on the 21st day. Milk and serum were collected for biochemical and hormonal analysis. The male and female offsprings were sacrified on the 14th and 21st day. The hormonal dosages were measured by radioimunassay. The animals were completely eviscerated to analyze body composition. Body mass (BM) and food intake were monitored during all experimental period. The SDG rats showed higher fat mass (+39%) while the OLSDG rats showed lower mineral content (-20%) and triglycerides (TG) serum levels (-39%). The SDG and OLSDG rats showed higher prolactin levels (+339% and +153% respectively) without changes in serum estradiol. On the 14th day of lactation we observed lower lactose (-17%) and protein (-20%) content in the OLSDG rats milk while in the SDG only lower protein (-21%). From the 13th day of lactation both the males and females OLSDG showed lower BM ( - 14%, - 16%, respectively). On the 14th day the male SDG and OLSDG showed lower fat mass (-24%, -55%, respectively), and the SDG offspring showed higher visceral fat mass (+39%). The SDG male also showed higher TG levels (+105%) and lower prolactin levels (-41%). The OLSDG males also showed lower prolactin serum levels (-41%). The OLSDG female showed higher serum estradiol at 14 days (+86% e +176%), which normalized at 21 days and higher cholesterolemia (+16%) and the SDG female presented higher TG levels (+74%). On day 21th day the male and female SDG and OLSDG showed lower TG levels (-48%,-54%, -42% and 59% respectively). Thus, the two main component of flaxseed showed biochemical and hormonal changes in the mothers and offspring, independent of gender. However, the changes observed in mothers differ from the offspring, and differ accordingly with the sex of offspring. The most impressive changes were the maternal hyperprolactinemia that can be one of the cause for the observed hypoprolactinemia in the offspring and the other main finding was the hypertriglyceridemia in the SDG group.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Avaliamos o efeito do consumo materno de SDG (Diglicosídeo Secoisolariciresinol) e de óleo de Linhaça+SDG sobre parâmetros bioquímicos e hormonais das ratas e das proles machos e fêmeas na lactação. As ratas lactantes foram separadas em: controle (C), ração controle cuja proteína foi caseína; (SDG): ração C com 400mg de SDG/Kg de ração; OLSDG: ração C com 400mg de SDG/Kg de ração e 7% de óleo de linhaça. No 14 e 20 dias de lactação as ratas foram ordenhadas e no 21 dia foram sacrificadas por punção cardíaca. Leite e soro foram coletados para avaliação bioquímica e hormonal. Hormônios foram quantificados por radioimunoensaio. As proles machos e fêmeas foram sacrificadas aos 14 e 21 dias de idade. Os animais foram eviscerados para análise da composição corporal. Monitoramos a ingestão alimentar e a massa corporal (MC) durante o período experimental. As ratas SDG apresentaram maior gordura corporal (GC; +39%), enquanto as OLSDG menor conteúdo mineral (-20%) e trigliceridemia (TG) (-39%). As ratas SDG e OLSDG apresentaram hiperprolactinemia (+389% e 153%, respectivamente) sem alteração na concentração de estradiol. No 14 dia de lactação, o leite das ratas OLSDG apresentou menores teores de lactose(-17%) e de proteínas (-20%) e o das ratas SDG apenas menor teor de proteína (-21%). A partir do 13 dia de lactação tanto os machos quanto as fêmeas OLSDG apresentaram menor MC (-14%, -16%, respectivamente). No 14 dia de lactação os machos SDG e OLSDG apresentaram menor gordura corporal (-24%, -55%, respectivamente ) e a prole SDG maior massa de gordura visceral (+39%). Os machos SDG apresentaram maiores concentrações de TG (+105%) e hipoprolactinemia (-41%). Os machos OLSDG também apresentaram hipoprolactinemia (-41%). As fêmeas SDG e OLSDG apresentaram maior estradiol aos 14 dias (+86% e +176%) que se normalizou aos 21 dias, maior colesterolemia (+16%) e as SDG apresentaram maior trigliceridemia (+74%). Aos 21 dias os machos e as fêmeas SDG e OLSDG apresentaram menor trigliceridemia (-48%, -54%,42% e -59%, respectivamente). Os dois componentes principais da semente de linhaça produzem alterações bioquímicas e hormonais tanto nas mães, quanto nas proles, independente do sexo. Entretanto, as alterações observadas diferem entre mães e prole e de acordo com o gênero. Entre as alterações mais importantes ressaltamos a hiperprolactinemia materna que pode ser um dos motivos para a hipoprolactinemia da prole e a hipertrigliceridemia causada pela ingestão de SDG pelas mães. / We evaluated the mothers intake of SDG (Diglicoside secoisolariciresinol) and flaxseed oil + SDG upon biochemical and hormonal parameters of lactating female rats and the male and female offspring during lactation. The female lactating rats were divided into: Control (C): feeding a diet with casein; (SDG): feeding diet C added 400mg of SDG/Kg diet; (OLSDG): diet C added 400mg of SDG/Kg diet and 7% of flaxseed oil. Milk samples were obtained on the 14th and 20th days of lactation and the mothers were sacrificed and blood collected by cardiac puncture on the 21st day. Milk and serum were collected for biochemical and hormonal analysis. The male and female offsprings were sacrified on the 14th and 21st day. The hormonal dosages were measured by radioimunassay. The animals were completely eviscerated to analyze body composition. Body mass (BM) and food intake were monitored during all experimental period. The SDG rats showed higher fat mass (+39%) while the OLSDG rats showed lower mineral content (-20%) and triglycerides (TG) serum levels (-39%). The SDG and OLSDG rats showed higher prolactin levels (+339% and +153% respectively) without changes in serum estradiol. On the 14th day of lactation we observed lower lactose (-17%) and protein (-20%) content in the OLSDG rats milk while in the SDG only lower protein (-21%). From the 13th day of lactation both the males and females OLSDG showed lower BM ( - 14%, - 16%, respectively). On the 14th day the male SDG and OLSDG showed lower fat mass (-24%, -55%, respectively), and the SDG offspring showed higher visceral fat mass (+39%). The SDG male also showed higher TG levels (+105%) and lower prolactin levels (-41%). The OLSDG males also showed lower prolactin serum levels (-41%). The OLSDG female showed higher serum estradiol at 14 days (+86% e +176%), which normalized at 21 days and higher cholesterolemia (+16%) and the SDG female presented higher TG levels (+74%). On day 21th day the male and female SDG and OLSDG showed lower TG levels (-48%,-54%, -42% and 59% respectively). Thus, the two main component of flaxseed showed biochemical and hormonal changes in the mothers and offspring, independent of gender. However, the changes observed in mothers differ from the offspring, and differ accordingly with the sex of offspring. The most impressive changes were the maternal hyperprolactinemia that can be one of the cause for the observed hypoprolactinemia in the offspring and the other main finding was the hypertriglyceridemia in the SDG group.

This thesis evaluated supplementation with two components of flaxseed during exercise training on inflammation in older adults.<P>Experiment 1: This experiment assessed secoisolariciresinol diglucoside (SDG) supplementation during aerobic exercise training on inflammation in older adults. Methods: One hundred subjects aged 50y or older were randomized to receive either SDG or placebo before completing a 6-month walking program. Fasting concentrations of interleukin-6 and tumor necrosis factor-á, glucose, triacylglycerol (TAG), high density lipoprotein (HDL), low density lipoprotein, and total cholesterol as well as leukocyte cell count were measured every two months while body composition, resting blood pressure, and a composite Z-score of six metabolic syndrome risk factors were assessed at baseline and 6 months. Results: Men on placebo increased metabolic syndrome composite Z-score (p<0.05). TAG increased (p=0.017) in men on placebo relative to men on SDG and men on SDG decreased (p=0.045) DBP relative to men on placebo. Conclusions: SDG had no effect on inflammation while it is effective in attenuating risk factors associated with metabolic syndrome in older males but not females.<p>Experiment 2: This experiment evaluated alpha-linolenic acid (ALA) supplementation during strength exercise training on inflammation in older adults. Methods: Fifty-one healthy older adults (65.4±0.8y) were randomized to receive ALA or a placebo before completing a 12 wk strength training program. Subjects were evaluated at baseline and 12 weeks for TNF-á and IL-6, muscle strength, body composition, and muscle thickness. Results: Males supplementing with ALA decreased IL-6 concentration (p=0.003). The female placebo and male ALA group had a significant increase in knee flexor thickness (p<0.05). Chest and leg press strength, lean tissue mass, and muscle thickness significantly increased, while percent fat and total body mass decreased with training (p<0.05), with no difference between ALA and placebo. Conclusions: ALA lowers IL-6 in older men, but has minimal effect on muscle mass and strength during resistance training.<p>General Conclusion: A composite score of metabolic syndrome is attenuated in males supplementing with SDG. ALA reduces IL-6 in older men. Older men, but not older women, derive specific health benefits from increased consumption of components of flaxseed consumed during an exercise program.