The discovery of new immunosuppressive drugs has resulted in an improvement of short-term graft survival. Despite this achievement, long-term cardiac allograft survival has not been correspondingly improved. Cyclosporine A (CsA), an effective immunosuppressive drug, has been shown to increase the risk of hyperlipidemia, hypertension, kidney injuries and chronic rejection despite its extensive use in the clinical setting. Therefore, these side-effects of CsA, may further contribute to graft failure over long-term. Early studies have shown that fish oil may reduce side-effects of CsA. These beneficial effects of fish oil may be related to n-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Flaxseed oil is another major source of an n-3 FA, namely α-linolenic acid (ALA). However, its impact on heart transplantation has not been fully explored. The current study aimed to investigate whether dietary flaxseed oil and fish oil reduce post-transplant complications and prolong graft function in a rat cardiac allograft model. Male Fischer and Lewis rats were used as donors and recipients, respectively, to generate a heterotopic cardiac allograft model. After transplant, animals were randomly assigned into 3 groups and fed a diet supplemented with: a) 5% w/w safflower oil (control n=7), b) 5% w/w flaxseed oil (n=8) or c) 2% w/w fish oil (n=7) and an intraperitoneal injection of cyclosporine A (CsA) (1.5 mg/kg/d) over 12 weeks. Body weight, blood pressure (BP), plasma levels of lipids, CsA, and select cytokines, fatty acid profile of hearts (native and graft) and liver tissues as well as graft function and chronic rejection features were assessed. Body weight and blood CsA levels were similar among the groups. As compared to controls, both diet treated groups demonstrated a significantly lower systolic blood pressure (SBP) (p<0.001), diastolic blood pressure (pressure (DBP) (p<0.001), mean arterial pressure (MAP) (p<0.001), heart rate (p<0.05), abdominal fat (p<0.05) and plasma levels of macrophage chemoattractant protein-1 (MCP-1) (p<0.05). Moreover, the fish oil group had significantly (p<0.05) lower plasma levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL), as compared to the control group. High-density lipoprotein cholesterol (HDL) concentrations were significantly higher (P<0.05) in the flaxseed oil-treated group as compared to the other two groups. Data of this study suggest that both flaxseed oil and fish oil may provide similar biochemical, hemodynamic and inflammatory improvements after heart transplantation; however, these apparent beneficial changes were not accompanied with significant reductions in chronic rejection states or apparent histological evidence of cyclosporine-induced nephrotoxicity in this model.

Studies had shown that leucine supplementation increases insulin sensitivity and it has been studied that n-3 PUFA may have an anti-inflammatory effect in adipocytes. However, the extent to which dietary sources such as leucine and/or n-3 PUFA act through PFKFB3/iPFK2 to suppress adipocyte inflammatory response has not been studied; PFKFB3/iPFK2 is a regulator that links adipocyte metabolism and inflammatory responses. In this study, the involvement of PFKFB3/iPFK2 in the effects of insulin sensitizing and anti-inflammatory effect of leucine and/or n-3 PUFA are explored using cultured 3T3-L1 adipocytes including wild-type cells, PFKFB3-control cells (iPFK2-Ctrl) and PFKFB3-knockdown cells (iPFK2-KD). In iPFK2-Ctrl cells, leucine supplementation appears to have insulin-sensitizing effects through improving p-Akt/Akt insulin signaling, but have no effect on adiponectin expression, and appear to have limited anti-inflammatory effects. n-3 PUFA supplementation appears to have limited effects on both insulin sensitizing and anti-inflammatory effects in iPFK2-Ctrl. In contrast, n-3 PUFA exhibit pro-inflammatory expression in iPFK2-KD. The results of this study support the hypothesis that PFKFB3/iPFK2 is critically involved in insulin-sensitizing effects of leucine. This role of PFKFB3/iPFK2, however, appears to be independent of anti-inflammatory responses. Given this, it is likely that PFKFB3/iPFK2 only account, in part, for the beneficial effects of leucine. n-3 PUFA stimulate PFKFB3/iPFK2 activity in wild-type adipocytes. However, PUFA do not exhibit anti-inflammatory and insulin-sensitizing effects in controls. In contrast, n3-PUFA exhibit proinflammatory effects in iPFK2-KD cells. Taken together, PFKFB3/iPFK2 is involved, at least in part, in the effects of insulin sensitization of leucine and appears to protect adipocytes from inflammatory responses, which could be exacerbated by n-3 PUFA when PFKFB3/iPFK2 is disrupted.

The discovery of new immunosuppressive drugs has resulted in an improvement of short-term graft survival. Despite this achievement, long-term cardiac allograft survival has not been correspondingly improved. Cyclosporine A (CsA), an effective immunosuppressive drug, has been shown to increase the risk of hyperlipidemia, hypertension, kidney injuries and chronic rejection despite its extensive use in the clinical setting. Therefore, these side-effects of CsA, may further contribute to graft failure over long-term. Early studies have shown that fish oil may reduce side-effects of CsA. These beneficial effects of fish oil may be related to n-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Flaxseed oil is another major source of an n-3 FA, namely α-linolenic acid (ALA). However, its impact on heart transplantation has not been fully explored. The current study aimed to investigate whether dietary flaxseed oil and fish oil reduce post-transplant complications and prolong graft function in a rat cardiac allograft model. Male Fischer and Lewis rats were used as donors and recipients, respectively, to generate a heterotopic cardiac allograft model. After transplant, animals were randomly assigned into 3 groups and fed a diet supplemented with: a) 5% w/w safflower oil (control n=7), b) 5% w/w flaxseed oil (n=8) or c) 2% w/w fish oil (n=7) and an intraperitoneal injection of cyclosporine A (CsA) (1.5 mg/kg/d) over 12 weeks. Body weight, blood pressure (BP), plasma levels of lipids, CsA, and select cytokines, fatty acid profile of hearts (native and graft) and liver tissues as well as graft function and chronic rejection features were assessed. Body weight and blood CsA levels were similar among the groups. As compared to controls, both diet treated groups demonstrated a significantly lower systolic blood pressure (SBP) (p<0.001), diastolic blood pressure (pressure (DBP) (p<0.001), mean arterial pressure (MAP) (p<0.001), heart rate (p<0.05), abdominal fat (p<0.05) and plasma levels of macrophage chemoattractant protein-1 (MCP-1) (p<0.05). Moreover, the fish oil group had significantly (p<0.05) lower plasma levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL), as compared to the control group. High-density lipoprotein cholesterol (HDL) concentrations were significantly higher (P<0.05) in the flaxseed oil-treated group as compared to the other two groups. Data of this study suggest that both flaxseed oil and fish oil may provide similar biochemical, hemodynamic and inflammatory improvements after heart transplantation; however, these apparent beneficial changes were not accompanied with significant reductions in chronic rejection states or apparent histological evidence of cyclosporine-induced nephrotoxicity in this model.

The aim of my thesis was to assess the influence of polyunsaturated fatty acids n 3 (DHA and EPA) on gene expression, mainly PPARy, in model organism. The expression of PPARy gene is increased by these polyunsaturated fatty acids and thus they decrease the risk of development of inflammation and atherosclerosis. This hypothesis was tested on 40 test rats (Wistar albino). The first 7 weeks the rats were fed with a diet containing beef tallow and sweet condensed milk until they manifested mild obesity and inflammation. During other 7 weeks they were divided into 4 groups, each containing 10 individuals. One of the groups was further fed with diet containing beef tallow (control group), other groups received diet with 6% content of oil from safflower added, 6% content of fish oil (high content of EPA) or 6% content of oil from Schizochytrium alga (high content of DHA). The expression of PPARy was measured by using molecular-biology methods at the end of the trial. It was proven that the diet rich on DHA increases PPARy gene expression (P<0,05). The increase of PPARy gene expression in a diet containing fish oil was inconclusive (P>0,05). With these results we confirmed the hypothesis that diet rich on PUFA n3 decreases the risk of inflammation development and atherosclerosis and that DHA is significantly more effective.

Background: Postpartum depression (PPD) is a complex mental health disorder that affects women during their childbearing years. It is a serious medical condition that occurs in approximately 13–20% of women after birth and has an adverse effect on both the mother and the infant. Certain dietary deficiencies in a pregnant or postnatal woman’s diet may cause postnatal depression. It is unclear whether Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are effective for treating or preventing PPD. Objectives: To assess the best available evidence to date regarding the effect of n-3 PUFAs on the etiology, prevention and treatment of postnatal depression. Methods: A systematic review and narrative synthesis was conducted in order to address the gaps in knowledge. For the systematic review, a broad search of electronic databases of published quantitative literature was conducted. Quality appraisal was performed using the tools produced by the effective public health practice project (EPHPP). The narrative synthesis consists of four elements: 1) developing a theory; 2) developing a preliminary synthesis; 3) exploring relationships in the data; 4) assessing the robustness of the synthesis. Results: Out of 181 potential articles, a total of 17 studies met the inclusion criteria. The overwhelming majority of the studies found that n-3 PUFAs had no association with PPD evaluations versus only few ones observed a beneficial effect of n-3 PUFAs supplementation on depressive symptoms. Significant heterogeneity was observed among included studies which can be explained by dissimilar study designs, differences in study duration, time period of measurement and number of participants, and in varied dosages and types of supplemental n-3 PUFAs. Conclusions: Overall, This systematic review and narrative synthesis failed to find a significant positive association between n-3 PUFAs intake and PPD. However further investigation of the specific molecular mechanisms underlying the function of n-3 PUFAs in the brain and the factors related to the pathophysiological nature of depression is warranted.

The aim of this study was to determine whether there is an influence of the active components of the fish oil, in particular polyunsaturated fatty acids n3 (PUFA n3) on expression of selected proteins which modulate the inflammatory response in model organisms pig. In the n3 PUFA is to assume that over signaling pathway PPARgamma, NFkappaB, increase adiponectin production, inhibit the production of proinflammatory cytokines, increase antiinflammatory cytokines production, thereby suppressing the inflammatory response in the body. This hypothesis was tested on 32 pigs, which were divided into two groups of 16 pieces in each group. The first experimental group was fed the basic feed mixture enriched with 2.5% fish oil (F) and the second control group was fed the basic feed with 2.5% palm oil (P). Last day of fattening pigs were 8 F and 8 P pigs intravenously application lipopolysaccharide (LPS) to induce an inflammatory response, the rest of group left without LPS stimulation, followed by intramuscular application of anesthetics and defeat. By Western blot was measured protein expression PPARgamma and NFkappaB in selected tissues, by ELISA concentration of adiponectin in plasma and by multiplex analysis plasma levels of cytokines. The results indicate that PPARgamma concentration in the F adipocytes after LPS stimulation tended to increase by 21% in comparison with P control stimulation with LPS, but the result was not statistically significant (P> 0.05; P = 0.11). Further, the F pigs stimulation with LPS as compared with intact F counterparts trend toward increased plasma levels of adiponectin by 18%, which was likely a reflection of the tendency to higher values in adipocytes by 18% (P> 0.05, p = 0.12), result was not statistically significant. Plasma adiponectin took on the same values of 21.1 ng x mL-1 in experimental and control groups (P> 0.05). Elevation (P <0.05) of NFkappaB in fatty tissue F pigs after LPS stimulation. In addition, the plasma level of anti-inflammatory IL4 and IL10 interleukins, as well as the proinflammatory cytokine TNFalfa, was increased (P <0.05) in the F group of pigs stimulated with LPS. The results of the present experiment are thus ambiguous. The hypothesis of the effect of fish oil or n3 PUFA to suppress the inflammatory response cannot this experiment conclusively confirmed.

No / Because of confounding factors, the effects of dietary n-3 polyunsaturated fatty acids (PUFA) on type 1 diabetes remain to be clarified. We therefore evaluated whether fat-1 transgenic mice, a well-controlled experimental model endogenously synthesizing n-3 PUFA, were protected against streptozotocin (STZ)-induced diabetes. We then aimed to elucidate the in vivo response at the pancreatic level. Beta-Cell destruction was produced by multiple low-doses STZ (MLD-STZ). Blood glucose level, plasma insulin level, and plasma lipid analysis were then performed. Pancreatic mRNA expression of cytokines, the monocyte chemoattractant protein, and GLUT2 were evaluated as well as pancreas nuclear factor (NF)-kB p65 and inhibitor of kB (IkB) protein expression. Insulin and cleaved caspase-3 immunostaining and lipidomic analysis were performed in the pancreas. STZ-induced fat-1 mice did not develop hyperglycemia compared with wild-type mice, and Beta-cell destruction was prevented as evidenced by lack of histological pancreatic damage or reduced insulin level. The prevention of Beta-cell destruction was associated with no proinflammatory cytokine induction (tumor necrosis factor-alpha, interleukin-1Beta, inducible nitric oxide synthase) in the pancreas, a decreased NF-kB, and increased IkB pancreatic protein expression. In the fat-1-treated mice, proinflammatory arachidonic-derived mediators as prostaglandin E2 and 12-hydroxyeicosatetraenoic acid were decreased and the anti-inflammatory lipoxin A4 was detected. Moreover, the 18-hydroxyeicosapentaenoic acid, precursor of the anti-inflammatory resolvin E1, was highly increased. Collectively, these findings indicate that fat-1 mice were protected against MLD-STZ-induced diabetes and pointed out for the first time in vivo the beneficial effects of n-3 PUFA at the pancreatic level, on each step of the development of the pathology-inflammation, Beta-cell damage-through cytokine response and lipid mediator production.

L’équilibre alimentaire entre les AGPI n-6 et les AGPI n-3 joue probablement un rôle important dans le fonctionnement du système nerveux central et notamment dans la régulation de la neurotransmission. Des études suggèrent qu’une déficience en AGPI n-3 renforcerait la sensibilité des individus à des agressions de type chronique, tel que le stress ou le vieillissement. Notre objectif était de caractériser l’impact des apports alimentaires en AGPI n-3 sur la réponse à un stress chronique. Pour cela, la régulation de paramètres biochimiques, comportementaux et électrophysiologiques par un stress chronique de contention a été évaluée chez le rat recevant différents apports alimentaires en AGPI n-3 (déficients en AGPI n-3 ; équilibrés ; enrichis en AGPI-LC n-3). L’influence des glucocorticoïdes (hormones impliquées dans la réponse au stress) et des AGPI sur des fonctions cellulaires participant à la transmission synaptique a été analysée in vitro par des mesures de libération de neurotransmetteurs sur la lignée neuroblastique SH_SY5Y et par l’analyse des propriétés régulatrices astrocytaires en culture primaire.Nos résultats montrent que, chez le rat, la réponse au stress est modulée par les apports alimentaires en AGPI n-3 : la déficience en AGPI n-3 accentue la sensibilité au stress, notamment la réduction de l’activité locomotrice et la sensibilité aux environnements anxiogènes ; à l’inverse, l’enrichissement en AGPI-LC n-3 atténue la réponse au stress chronique, en réduisant la perte de poids, le pic de corticostérone plasmatique et la réponse émotionnelle. Comme le suggèrent les résultats obtenus in vitro, ces effets sont liés à des régulations complexes par les AGPI et les glucocorticoïdes des paramètres de libération de neurotransmetteur, de la plasticité morphologique astrocytaire et de la capacité de capture du glutamate par les astrocytes. / Dietary balance between n-6 PUFA and n-3 PUFA probably plays a major role in the regulation of brain function. Some studies suggest that an n-3 PUFA deficiency exacerbates the sensitivity of individuals to emotional disturbances, such as chronic stress. The aim of our work was to determine the impact of n-3 PUFA dietary intakes on stress response. The regulation of biochemical, electrophysiological and behavioural parameters by chronic restraint stress has been evaluated in rats receiving different n-3 PUFA supplies (n-3 PUFA deficient, balanced, n-3 LC-PUFA enriched). In parallel, we have conduced an in vitro study to characterize the effects of glucocorticoids (one of the major hormone involved in stress response) and of PUFA on the release of neurotransmitter (in human neuroblastoma SH_SY5Y cells) and on several astrocytic properties involved in synaptic regulation (in primary culture of rat astrocytes). In rats, we have shown that stress response is modulated by the n-3 PUFA status: the n-3 PUFA deficiency exacerbated the sensibility to stress, by aggravating the reduction of locomotor activity and the sensibility to anxiogenic environment; conversely, the n-3 LC-PUFA enrichment reduced rat responses to chronic stress, by limiting the weight loss, the increase in plasma corticosterone and the emotional response. As suggested by the results obtained in vitro, these effects are linked to complex influences of PUFA and glucocorticoids on the release of neurotransmitter and on astroglial morphological plasticity and glutamate uptake capacity.

Obesity and associated metabolic disorders, called as "metabolic syndrome", currently represent a major social and economical problem of public health. From the energy balance point of view, long-lasting energy surplus leads eventually to massive accumulation of energy stores resulting in various adverse effects on metabolism and health. General goal of the thesis was to examine these metabolic disorders at cellular and whole-body level using suitable mouse models. The main focus was on the most metabolically active tissue, namely skeletal muscle, liver and adipose tissue and on the regulatory roles of AMP-activated protein kinase (AMPK) and leptin in the energy metabolism. The whole thesis is based on four published studies. Two studies were focused on skeletal muscle. In the first study, we proved the involvement of leptin and AMPK in the metabolic response to high-fat diet-feeding. We described a mechanism of muscle non- shivering thermogenesis based on enhanced lipid catabolism, which contributes to the genetically-determined resistance of inbred A/J mice to obesity. Such mechanism was not operating in obesity-prone C57BL/6 mice. In the second study, performed using C57BL/6 mice, we have described beneficial effect of combination treatment using n-3 polyunsaturated fatty acids (n-3 PUFA) of...

Foram utilizadas 168 galinhas poedeiras Hisex White em delineamento experimental inteiramente casualizado, com duração de cinco semanas. As aves foram distribuídas em sete tratamentos com três repetições cada, com o objetivo de verificar a influência da suplementação de três fontes marinhas de PUFAs n-3 - óleos de salmão (SA) e de atum e sardinha (A/S) e mistura de algas marinhas (AL), bem como sua combinações (SA+A/S, AL+SA, AL+A/S) - em relação ao grupo controle alimentado com ração basal de milho e soja (CON), sobre a qualidade do ovo e a composição lipídica da gema. A qualidade externa e interna do ovo não foi alterada significativamente pela adição de fontes de PUFAs n-3 na dieta das aves. A relação entre os lípides saturados : monoinsturados : poliinsaturados da gema (3,5 : 4,5 : 2,0) manteve-se constante com a adição dos suplementos de PUFAs n-3 na ração. Os óleos de salmão (SA) e de atum e sardinha (A/S) revelaram-se mais efetivos no enriquecimento da gema do ovo em PUFAs n-3, em especial o DHA. A relação PUFAs n-6/ PUFAs n-3 sofreu redução significativa com a adição das fontes marinhas de ômega-3 à dieta das galinhas. O EPA, embora em teores mais baixos que o DHA na gema do ovo, apresentou incremento significativo com o uso dos óleos de peixes (SA e A/S) adicionado à dieta em relação ao CON. O consumo de dois ovos enriquecidos com DHA do presente estudo, por dia, provavelmente atenderia os requerimentos diários deste PUFA n-3 para o ser humano / To investigate the influence of three PUFAs n-3 marine sources - salmon oil (SA), tuna and sardine oil (A/S), marine algae (AL) and combinations (SA+A/S, AL+SA, AL+A/S) - on egg quality and egg lipid composition, compared to a corn/soy control group (CON), 168 Hisex White laying hens were assigned into seven treatments with three repetitions in a randomized design during a experimental period of five weeks. The external and internal egg quality were not significantly affected by the addition of PUFAs n-3 marine sources into the hen diets. The saturated : monounsaturated : polyunsaturated ratio (3.5:4.5:2.0) remained constant by the supplementation of the marine sources into the diets. The salmon oil and the tuna and sardine oil showed the best results of PUFAs n-3 egg yolk enrichment, mainly the DHA. The PUFAs n-6/PUFAs n-3 ratio was significantly reduced by the inclusion of PUFAs n-3 sources into the hen diets. The EPA, although with lower levels than DHA into the egg yolk, showed a significant increase by the use of salmon oil and tuna and sardine oil added to the diet as compared to the control group (CON). The consumption of two DHA enriched eggs from this study per day probably would reach the daily requirements of this PUFA n-3 for the human been