Introduction : L’apolipoprotéine E (ApoE) est une protéine membranaire impliquée dans le catabolisme des lipoprotéines riches en triglycérides (TG). Le polymorphisme du gène de l’apolipoprotéine E epsilon 4 (APOE4) est considéré comme le plus grand facteur de risque génétique de la maladie d’Alzheimer tardive. Il est connu que la consommation d’acide gras polyinsaturé oméga 3 (AGPI n-3) serait associée à une diminution du risque de déclin cognitif. L’acide docosahexaénoïque (DHA) est un AGPI n-3 contenu dans les poissons riches en gras. Des résultats publiés par la professeure Mélanie Plourde ont démontré que suite à une diète riche en DHA, la concentration plasmatique en DHA était 3 fois moins élevée chez les porteurs de l’APOE4. Cela laisse supposer que les porteurs d’APOE4 auraient possiblement une perturbation dans l’homéostasie des AGPI n-3 au niveau entérocytaire. Objectif : Déterminer le profil en acides gras (AG) dans le duodénum et le jéjunum selon la diète et le polymorphisme de l’APOE chez le modèle animal murin. Évaluer si la diète et/ou le polymorphisme de l’APOE affectent l’expression protéique des transporteurs d’AG dans le jéjunum chez le modèle animal murin. Matériel et méthodes : Des souris knock-in pour les différentes formes de l’APOE (APOE3 ou APOE4) ont été utilisées. À 4 mois, celles-ci ont reçu pendant 8 mois soit une diète contrôle ou une diète riche en DHA. Après sacrifice des animaux, le duodénum et le jéjunum ont été prélevés. Une extraction des lipides totaux par la méthode de Folch a été effectuée. Le profil en AG a ensuite été réalisé par chromatographie en phase gazeuse. L’expression protéique des transporteurs d’AG entérocytaire a été mesurée par immunobuvardage de type western. Résultats et discussion : Les souris nourries avec la diète DHA avaient une augmentation en DHA dans le duodénum et le jéjunum établissant ainsi que le DHA est bien absorbé par les entérocytes dans ce modèle animal. Le génotype de l’APOE ne semble pas affecter spécifiquement le métabolisme du DHA puisqu’aucune différence significative n’a été observée pour le génotype. Par ailleurs, les souris ayant consommé la diète DHA avaient une diminution en acide arachidonique. Cette diminution semble plus prononcée chez les souris porteuses de l’APOE4, ce qui pourrait suggérer une demande plus importante en DHA chez les souris porteuses de l’APOE4. D’autre part, les souris nourries avec la diète DHA avaient une augmentation significative de l’expression relative des transporteurs d’AG Cd36 et Fabp2. Finalement, le transporteur d’AG Fabp1 tend à être diminué chez les souris porteuses de l’APOE4 Conclusion : Ces résultats suggèrent une possible perturbation dans le transit et l’exportation des AG sous forme de chylomicron plutôt que dans l’absorption de ceux-ci.

In my study thesis Effect of eikosapentaenoic and dokosahexaenoic acids on expression of selected genes, which participate in modulation of inflammatory reaction at model organism I evaluated expression of genes GPR120, PPARgamma, LBP, ICAM, Il-4, Il-10, Il-1beta and TGF-beta. As model organism was selected pig. The pigs were divided in two groups, the control group was fed with 2,5% addition of palmic oil (P), the second group was fed with 2,5% addition of fish oil. After 70 days long fattening was each group divided into halfs. One half of each group was stimulated LPS (P+ and R+). Liver and adipose tissue were collected, mRNA was isolated (Rneasa Mini Kit), after reverse transcription the expression was measured by quantitative RT-PCR. By almost every genes there was increase in expression after LPS stimulation in groups P+ and R+. between P- and R- the expression was same or a little bit higher in R-. R+ was allways bigger than R-. The hypothesis were that EPA and DHA should reduce expression in inflammation. This hypothesis was not proofed. I recomend further studies with the same model organism to refill the results.

Aim: The purpose of this study was to investigate the influence of docosahexaenoic acid (DHA) on muscle damage and inflammation following an acute eccentric exercise bout. Methods: A double-blind placebo-controlled, study was performed using 41 healthy, untrained males aged 18-28 y who consumed either 2 g/d DHA or placebo (PL, corn oil) for 32 days. Supplements were consumed for 28 days prior to exercise. Participants completed an eccentric exercise procedure of the elbow flexors at 140% of 1-RM (6 sets x 10 repetitions). The time under tension (TUT) for each set of eccentric contractions was recorded manually from the investigators voice commands. Fasted blood samples for prostaglandin E2 (PGE2), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL1-ra), C-reactive protein and creatine kinase (CK) were assessed on days 1, 2 and 4. Fasted serum DHA was measured at baseline (day -28) and on day 1. Peak isometric strength of the elbow flexors, delayed-onset muscle soreness, and range of motion were measured on day 1 prior to exercise and days 2, 3, and 4 following exercise. Results: DHA significantly reduced natural log of CK (p<0.05) response over 4 d. Additionally, IL-6 area under the curve (AUC) was reduced for DHA compared to PL (3.6 ± 2.5 pg/mL vs. 5.3 ± 2.7 pg/mL) (p<0.05). TUT/set was higher in the DHA group compared to placebo (p<0.05). There were no other significant differences between treatments. Conclusion: DHA supplementation produced lower indicators of muscle damage (CK) and inflammation (IL-6 AUC). DHA supplementation resulted in greater TUT/set. / Master of Science

L'acide docosahexaénoïque (DHA) est un acide gras polyinsaturé oméga-3 (AGPI [oméga]3) concentré dans le poisson. Il est l'AGPI [oméga]3 présent en plus grande quantité dans le cerveau. Une étude épidémiologique a démontré que la consommation de deux portions de poisson par semaine peut ralentir le rythme du déclin cognitif qui survient avec le vieillissement. Étude SUPPLÉMENT. Objectif : Évaluer le changement plasmatique en AGPI [oméga]3 chez des sujets jeunes et âgés lors d'une supplémentation en acide eicosapentaénoïque (EPA)/DHA. Résultats : Chez les sujets jeunes et âgés, le DHA (73 « 47% et 117 « 68 %) et l'EPA (133 « 67% et 97 « 52%) plasmatiques ont augmenté significativement (p < 0,05) avec la supplémentation. Le pourcentage de DHA était supérieur chez les sujets âgés par rapport aux sujets jeunes avec la supplémentation. Conclusion : Les différences observées entre les sujets jeunes et âgés suggèrent qu'il existe un changement dans le métabolisme du DHA avec le vieillissement. Étude TRACEUR. Objectif : Évaluer l'incorporation du DHA marqué au carbone 13 (indice supérieur 13]C-DHA) dans les lipides totaux plasmatiques et sa [bêta]-oxydation chez des participants jeunes et âgés en bonne santé. Résultats : Initialement, la concentration de DHA dans les lipides totaux plasmatiques était similaire entre les groupes. Le [indice supérieur 13]C-DHA avait tendance (p = 0,055) à s'incorporer davantage chez les participants âgés (0,80 « 0,35 nmol/ml) comparativement aux jeunes (0,35 « 0,12 nmol/ml) quatre heures après la prise du traceur. Conclusions : Ces résultats suggèrent que l'incorporation du DHA dans les lipides plasmatiques et sa [bêta]-oxydation dans les heures suivant son ingestion sont influencés par l'âge. La faible [bêta]-oxydation du DHA sur un mois montre qu'il est davantage conservé pour des rôles structuraux plutôt qu'à des fins énergétiques. Conclusion générale :L'âge est associé à une augmentation de l'incorporation du DHA dans les lipides plasmatiques qui se reflète par la plus grande augmentation du DHA dans le plasma lors d'une supplémentation chez des personnes âgées. À cause de sa plus grande incorporation, davantage de DHA est disponible pour la [bêta]-oxydation, ce qui explique la plus grande quantité de DHA [bêta]-oxydé chez les personnes âgées. Cependant la [bêta]-oxydation du DHA est trop faible pour entrer en contradiction avec les résultats obtenus lors de la supplémentation.--Résumé abrégé par UMI.

O avanço na expectativa de vida da população elevou concomitantente as manifestações de doenças neurodegenerativas, sendo Alzheimer a mais frequente. As condições clínicas mais importantes relacionadas aos pacientes acometidos por tal neurodegeneração, são as placas ?-amilóides, os emaranhados neurofibrilares e a extensa perda neuronal, ocasionadas por fatores genéticos e/ou ambientais. A alimentação pode ser um fator desencadeador de demência, pois, a baixa ou longa exposição aos pesticidas incorporados aos alimentos promovem neurodegenerações em decorrência do estresse oxidativo gerado por tais produtos químicos, desenvolvidos para alterar o metabolismo em organismos não viáveis comercialmente na agricultura, denominados como pragas. Desta forma, um sistema de neuroproteção se faz necessário para minimizar e/ou reverter os danos desencadeados por agrotóxicos incorporados em alimentos rotineiramente consumidos. / The advancement in the life expectancy of the population concomitantly increased the manifestations of neurodegenerative diseases, with Alzheimer being the most frequent. The most important clinical conditions related to the patients affected by such neurodegeneration are ?-amyloid plaques, neurofibrillary tangles and extensive neuronal loss, caused by genetic and / or environmental factors. Feeding can be a trigger for dementia since the low or long exposure to pesticides incorporated into foods promote neurodegenerations due to the oxidative stress generated by such chemicals, designed to alter the metabolism in non-commercially viable organisms in agriculture, known as pests In this way, a neuroprotection system is necessary to minimize and / or reverse the damage caused by pesticides incorporated into routinely consumed foods.

O presente trabalho foi composto de dois estudos distintos. O Estudo I, com um foco conservacionista, teve como objetivo a avaliação e comparação de diferentes métodos de criopreservação de sêmen de bugio-preto (Alouatta caraya). Para tanto, o estudo foi dividido em dois experimentos: Experimento I composto de dois ensaios no primeiro ensaio foram comparados dois diluidores comerciais BotuBOV e Test-yolk buffer (TYB) e no segundo ensaio foram comparados dois métodos de criopreservação de sêmen congelação lenta e vitrificação; Experimento II avaliação dos efeitos da adição de DHA e de Trolox (análogo da vitamina E) ao diluidor para criopreservação de sêmen. O diluidor TYB apresentou melhores resultados quando comparados ao BotuBOV. A congelação lenta apresentou melhores resultados quando comparada à vitrificação. Não houve diferença entre o diluidor controle e os diluidores com Trolox, DHA ou combinação dos dois (DHAT), com exceção da integridade de acrossoma, que foi significativamente menor para o diluidor DHAT. Conclui-se que são necessários mais estudos, com utilização de outras doses de DHA e Trolox, além de outros antioxidantes. O Estudo II, com foco em pesquisa biomédica, teve como objetivo a criopreservação de sêmen de macaco-rhesus (Macaca mulata) e avaliação da qualidade pós-descongelação por meio de fecundação in vitro (FIV). Para tanto, o estudo foi dividido em três experimentos: Experimento I avaliação e comparação de dois métodos de criopreservação de sêmen congelação lenta e vitrificação; Experimento II avaliação e comparação de quatro métodos de preparação do sêmen pós-descongelação lavagem simples (LS), swim-up (SU), separação por gradiente de densidade (SGD) e filtragem em lã de vidro (FLV); Experimento III avaliação da qualidade seminal pós-descongelação por meio de FIV. A congelação lenta apresentou melhores resultados que a vitrificação (p<0,05). LS apresentou os melhores resultados, seguido por SGD e SU, enquanto FLV apresentou os piores resultados. LS e SGD foram utilizados para avaliação da qualidade seminal por meio de FIV, utilizando sêmen fresco como controle. As taxas de fecundação (média±EPM%) para oócitos MI inseminados com sêmen fresco (43.5±16.4) foram significativamente maiores (p<0,05) que LS (2.0±2.0), mas não diferiram de SGD (25.1±14.2). Não houve diferença na taxa de blastocistos (média±EPM%) entre os tratamentos (variação de 0 a 11.9±7.9). As taxas de fecundação para oócitos MII inseminados com sêmen fresco (41.4±3.6) também foram significativamente maiores que SGD e LS (18.4±6.9 e 12.7±7.7, respectivamente), assim como a taxa de blastocistos (64.7±13.6; 4.7±4.7; 30.9±13.8, respectivamente). Conclui-se que, espermatozoides criopreservados foram capazes de fertilizar oócitos e os embriões atingiram o estágio de blastocisto. A SGD selecionou espermatozoides pós-descongelação de melhor qualidade para FIV em macacos-rhesus, quando comparada à LS / This work was divided in two studies. The objective of Study I was to test and compare different cryopreservation methods for sperm from black-and-gold howler monkeys (Alouatta caraya), with a focus on species conservation. The study was divided in two experiments. Experiment I composed of two trials the first trial compared two commercial extenders BotuBOV and Test-yolk buffer (TYB), and the second trial compared two cryopreservation methods slow freezing and vitrification; Experiment II evaluation of the effects of DHA and Trolox (vitamin E analog) as additives to the freezing extender. TYB had better results when compared to BotuBOV. Slow freezing had better results when compared to vitrification. There was no difference between control extender (TYB) and extender containing Trolox, DHA or a combination of both (DHAT), except for acrosome integrity, which was significantly lower for DHAT. In conclusion, more studies are necessary, using other doses of DHA and Trolox, as well as other antioxidants. The objective of Study II was to assess the quality of frozen-thawed sperm from rhesus macaques (Macaca mulatta) by in vitro fertilization (IVF). The study was divided in three experiments. Experiment I evaluation and comparison of two cryopreservation methods slow freezing and vitrification; Experiment II evaluation and comparison of four preparation methods for frozen-thawed sperm simple wash (SW), swim-up (SU), density gradient centrifugation (DGC), and glass wool filtration (GWF); and Experiment III evaluation of frozen-thawed sperm quality by IVF. Slow freezing had better results when compared to vitrification (p<0,05). SW had better results, followed by DGC and SU, while GWF had the worse results. SW and DGC were further evaluated by IVF. Fertilization rates (mean±SEM%) with MI oocytes using fresh sperm were significantly higher (43.5±16.4) than with SW (2.0±2.0) and did not differ from DGC (25.1±14.2). There was no difference in blastocyst rates between treatments (range 0 to 11.9±7.9). Fertilization rates with MII ova were also significantly higher with fresh sperm (41.4±3.6) than DGC and SW (18.4±6.9 and 12.7±7.7, respectively), and more blastocysts developed from MIIs fertilized with fresh sperm (64.7±13.6) than SW and DGC (4.7±4.7 and 30.9±13.8, respectively). In conclusion, frozen-thawed sperm were able to fertilize oocytes and embryos reached the blastocyst stage. DGC yielded better frozen-thawed sperm for IVF in rhesus macaques, when compared with SW

Existe um grande potencial para a expansão da produção de microalgas, tanto pela variedade de usos quanto pelos produtos que delas podem ser derivados. Dentre esses usos, as características nutricionais e funcionais conferem às algas alto valor biológico para uso em nutrição humana e animal. No entanto, são poucos os estudos que avaliam seu potencial na nutrição de peixes, mais especificadamente de tilápia, um dos principais produtos da aquicultura mundial. O objetivo deste trabalho foi avaliar o potencial de uso de duas espécies de microalgas e o nível ótimo de inclusão da Schizochytrium em dietas para a tilápia. Para tanto, foram realizados ensaios para avaliação do coeficiente de digestibilidade aparente (CDA) de uma microalga rica em proteína, Chlorella sorokiniana, e outra rica em energia, a Schizochytrium sp., ao longo de ensaios de desempenho e digestibilidade de rações contendo níveis crescentes (0%; 1%; 2,5%; 5%; 7,5% e 10%) de Schizochytrium sp. a fim de determinar o nível ótimo de inclusão nas dietas. As microalgas apresentaram altos coeficientes de digestibilidade para a tilápia, com CDA para a proteína de 90,51 e 97,20 % e para energia de 84,22 e 82,55 %, para a Chlorella e Schizochytrium, respectivamente. Os níveis crescentes de inclusão da Schizochytrium alteraram a digestibilidade das rações de forma decrescente para a proteína, passando de um CDA de 88,07 para 86,01, e energia, de um CDA de 74,19 para 67,35. No ensaio de desempenho foi registrado aumento no consumo de ração e piora na conversão alimentar aparente, sem que outros parâmetros de desempenho zootécnico fossem alterados, à medida que aumentava os níveis de inclusão da Schizochytrium na dieta. Não foram registradas alterações nos conteúdos de macro nutrientes na carcaça dos peixes, no entanto, os níveis crescentes de inclusão alteraram o perfil de ácidos graxos aumentando a quantidade de ácidos graxos n-3 no filé, principalmente do ácido docosaexaenoico (DHA), e redução na relação n-6/n-3. Dessa forma, é possível a utilizar Schizochytrium sp. como aditivo nas dietas para alteração do perfil de ácidos graxos da tilápia, enriquecendo os filés com ácidos graxos n-3, com pouco prejuízo nos parâmetros de desempenho. / There is a great potential for expand the microalgae production as by the variety of it uses as for the products and processes which may derive from them. Amongst such uses, nutritional and functional characteristics provide them a high biological value for use in human and animal nutrition. Nevertheless, few studies have evaluated their potential for fish nutrition more specifically tilapia, which is one of the main aquaculture products in the world. The aim of this research was to evaluate the potential use of two microalgae and the optimal level of inclusion of Schizochytrium in diets for tilápia. Therefore, tests were conducted to evaluate the apparent digestibility coefficient (ADC) of microalgae with high protein content Chlorella sorokiniana and another with high energy, Schizochytrium sp. and also performance assay and feed digestibility containing inclusion levels (0%, 1%, 2.5%, 5%, 7.5% and 10%) of Schizochytrium in order to determine the optimum addition level. Both species were very digestible for tilapia with ADCs for protein of 90.51 and 97.20 and for energy 84.22 and 82.55 to Chlorella and Schizochytrium respectively. The increasing levels of inclusion of Schizochytrium changed the digestibility of feed for the protein, through a ADC from 88.07 to 86.01 and for energy from 74.19 to 67.35 ADC. In the growth test as the inclusion of Schizochytrium increased there was an increase in feed intake and feed conversion ratio but any other growth parameters were changed. Regarding the carcass composition, there were no changes in macronutrients composition however, the increasing levels of Schizochytrium altered the fatty acid profile by increasing the amount of omega 3 mainly docosahexaenoic acid (DHA) and reduced the n-6/n-3 ratio. Thus, it is possible to use the Schizochytrium to modify the fatty acid profile of tilápia by incorporating omega 3, with little loss in performance parameters.

O presente trabalho foi composto de dois estudos distintos. O Estudo I, com um foco conservacionista, teve como objetivo a avaliação e comparação de diferentes métodos de criopreservação de sêmen de bugio-preto (Alouatta caraya). Para tanto, o estudo foi dividido em dois experimentos: Experimento I composto de dois ensaios no primeiro ensaio foram comparados dois diluidores comerciais BotuBOV e Test-yolk buffer (TYB) e no segundo ensaio foram comparados dois métodos de criopreservação de sêmen congelação lenta e vitrificação; Experimento II avaliação dos efeitos da adição de DHA e de Trolox (análogo da vitamina E) ao diluidor para criopreservação de sêmen. O diluidor TYB apresentou melhores resultados quando comparados ao BotuBOV. A congelação lenta apresentou melhores resultados quando comparada à vitrificação. Não houve diferença entre o diluidor controle e os diluidores com Trolox, DHA ou combinação dos dois (DHAT), com exceção da integridade de acrossoma, que foi significativamente menor para o diluidor DHAT. Conclui-se que são necessários mais estudos, com utilização de outras doses de DHA e Trolox, além de outros antioxidantes. O Estudo II, com foco em pesquisa biomédica, teve como objetivo a criopreservação de sêmen de macaco-rhesus (Macaca mulata) e avaliação da qualidade pós-descongelação por meio de fecundação in vitro (FIV). Para tanto, o estudo foi dividido em três experimentos: Experimento I avaliação e comparação de dois métodos de criopreservação de sêmen congelação lenta e vitrificação; Experimento II avaliação e comparação de quatro métodos de preparação do sêmen pós-descongelação lavagem simples (LS), swim-up (SU), separação por gradiente de densidade (SGD) e filtragem em lã de vidro (FLV); Experimento III avaliação da qualidade seminal pós-descongelação por meio de FIV. A congelação lenta apresentou melhores resultados que a vitrificação (p<0,05). LS apresentou os melhores resultados, seguido por SGD e SU, enquanto FLV apresentou os piores resultados. LS e SGD foram utilizados para avaliação da qualidade seminal por meio de FIV, utilizando sêmen fresco como controle. As taxas de fecundação (média±EPM%) para oócitos MI inseminados com sêmen fresco (43.5±16.4) foram significativamente maiores (p<0,05) que LS (2.0±2.0), mas não diferiram de SGD (25.1±14.2). Não houve diferença na taxa de blastocistos (média±EPM%) entre os tratamentos (variação de 0 a 11.9±7.9). As taxas de fecundação para oócitos MII inseminados com sêmen fresco (41.4±3.6) também foram significativamente maiores que SGD e LS (18.4±6.9 e 12.7±7.7, respectivamente), assim como a taxa de blastocistos (64.7±13.6; 4.7±4.7; 30.9±13.8, respectivamente). Conclui-se que, espermatozoides criopreservados foram capazes de fertilizar oócitos e os embriões atingiram o estágio de blastocisto. A SGD selecionou espermatozoides pós-descongelação de melhor qualidade para FIV em macacos-rhesus, quando comparada à LS / This work was divided in two studies. The objective of Study I was to test and compare different cryopreservation methods for sperm from black-and-gold howler monkeys (Alouatta caraya), with a focus on species conservation. The study was divided in two experiments. Experiment I composed of two trials the first trial compared two commercial extenders BotuBOV and Test-yolk buffer (TYB), and the second trial compared two cryopreservation methods slow freezing and vitrification; Experiment II evaluation of the effects of DHA and Trolox (vitamin E analog) as additives to the freezing extender. TYB had better results when compared to BotuBOV. Slow freezing had better results when compared to vitrification. There was no difference between control extender (TYB) and extender containing Trolox, DHA or a combination of both (DHAT), except for acrosome integrity, which was significantly lower for DHAT. In conclusion, more studies are necessary, using other doses of DHA and Trolox, as well as other antioxidants. The objective of Study II was to assess the quality of frozen-thawed sperm from rhesus macaques (Macaca mulatta) by in vitro fertilization (IVF). The study was divided in three experiments. Experiment I evaluation and comparison of two cryopreservation methods slow freezing and vitrification; Experiment II evaluation and comparison of four preparation methods for frozen-thawed sperm simple wash (SW), swim-up (SU), density gradient centrifugation (DGC), and glass wool filtration (GWF); and Experiment III evaluation of frozen-thawed sperm quality by IVF. Slow freezing had better results when compared to vitrification (p<0,05). SW had better results, followed by DGC and SU, while GWF had the worse results. SW and DGC were further evaluated by IVF. Fertilization rates (mean±SEM%) with MI oocytes using fresh sperm were significantly higher (43.5±16.4) than with SW (2.0±2.0) and did not differ from DGC (25.1±14.2). There was no difference in blastocyst rates between treatments (range 0 to 11.9±7.9). Fertilization rates with MII ova were also significantly higher with fresh sperm (41.4±3.6) than DGC and SW (18.4±6.9 and 12.7±7.7, respectively), and more blastocysts developed from MIIs fertilized with fresh sperm (64.7±13.6) than SW and DGC (4.7±4.7 and 30.9±13.8, respectively). In conclusion, frozen-thawed sperm were able to fertilize oocytes and embryos reached the blastocyst stage. DGC yielded better frozen-thawed sperm for IVF in rhesus macaques, when compared with SW

Selon une étude précédente, une limitation à l'efficacité anticancéreuse du 5-Fluorouracile (5-FU) repose sur la sécrétion d'IL-1β par des cellules myéloïdes immunosuppressives (MDSC). La libération d'IL-1β mature provient de l'activation de NLRP3 induite par le 5- FU et de l’augmentation de l’activité de la caspase-1 dans les MDSC, qui favorise la reprise de la croissance tumorale chez des souris traitées avec 5-FU. L'acide docosahexaénoïque (DHA) appartient à la famille des acides gras oméga-3 et possède des propriétés anticancéreuses et anti-inflammatoires qui pourraient améliorer la chimiothérapie à base de 5-FU. Dans ces travaux, nous démontrons que le DHA inhibe la sécrétion d'IL 1β induite par le 5 FU dans une lignée cellulaire de MDSC (MSC-2). Chez des souris porteuses de tumeurs traitées par 5 FU, nous avons montré qu'un régime alimentaire enrichi en DHA réduit la concentration d'IL 1β circulante et la récidive tumorale après une injection de 5 FU. Le traitement par 5 FU conduit à l'activation de JNK dans les MDSC et l'inhibiteur de JNK SP600125 diminue la sécrétion d’IL-1β. De plus, le DHA est capable de contrecarrer l'activation de JNK induite par 5-FU dans les MDSC, entraînant la chute de la libération de l’IL 1β. De plus, nous avons montré que la supplémentation en DHA dans les MDSC exposées au 5 FU diminuait l’activité de la caspase-1 ainsi que la modification des interactions entre NLRP3 et la caspase-1, ASC ou β-arrestine-2. De manière inattendue, la régulation de l'activité de la caspase-1 par le DHA était indépendante de JNK, ce qui suggère que le DHA pourrait contrôler la sécrétion de l’IL 1β par le biais de l'inflammasome NLRP3 et de la voie JNK. Enfin, nous avons trouvé une corrélation négative entre la teneur en DHA dans le plasma et l'induction du niveau d'IL 1β ou de la caspase-1 dans le sang de patients traités par chimiothérapie à base de 5-FU.L’ensemble de ces données fournissent de nouvelles informations sur la régulation de la sécrétion de l’IL-1β par le DHA et son bénéfice potentiel dans la chimiothérapie à base de 5-FU. / A limitation to 5-Fluorouracil (5-FU) anti-cancer efficacy relies on the secretion of IL-1β by myeloid-derived suppressor cells (MDSC) according to a previous pre-clinical report. The release of mature IL-1β originates from 5 FU mediated NLRP3 activation with increased caspase-1 activity in MDSC and sustains tumor growth recovery in 5 FU treated mice. Docosahexaenoic acid (DHA) belongs to omega-3 fatty acid family and harbors both anti cancer and anti inflammatory properties which might could improve 5 FU chemotherapy. Here, we demonstrate that DHA inhibits 5 FU induced IL 1β secretion produced by a MDSC cell line (MSC-2). In tumor-bearing mice treated with 5 FU, we showed that a DHA enriched diet reduces circulating IL 1β concentration and tumor recurrence after 5 FU injection. 5 FU treatment led to JNK activation in MDSC and JNK inhibitor SP600125 decreased IL 1β secretion. Moreover, DHA was able to counteract 5 FU mediated JNK activation in MDSC leading to the drop of IL 1β release. In addition, we showed that DHA supplementation in 5 FU exposed MDSC decreases caspase-1 activity along with a modification of the interactions between NLRP3 and caspase-1, ASC or β arrestin-2. Unexpectedly, the regulation of caspase-1 activity by DHA was independent of JNK which suggests that DHA could control IL 1β secretion through both NLRP3 inflammasome and JNK pathway. Interestingly, we found a negative correlation between DHA content in plasma and the induction of circulating IL 1β level or caspase-1 activity in patients treated with 5 FU based chemotherapy.Together, these data provide new insights on the regulation of IL 1β secretion by DHA and its potential benefit in 5-FU based chemotherapy.

Introduction: La consommation de poissons gras semble diminuer le risque de déclin cognitif lors du vieillissement. Cet effet serait potentiellement attribuable à deux acides gras oméga-3 concentrés dans le poisson: l'acide docosahexaénoïque (DHA) et l'acide eicosapentaénoïque (EPA). Cependant, ce lien n'est pas valide chez les personnes porteuses du génotype de l'apolipoprotéine E epsilon 4 (ApoE4), le facteur de risque génétique le plus important pour la maladie d'Alzheimer. Ces données suggèrent un débalancement dans le métabolisme du DHA chez les porteurs de l'ApoE4. Objectif: Évaluer si le polymorphisme de l'ApoE4 débalance le métabolisme d'un traceur DHA marqué au carbone 13 ([indice supérieur 13] C-DHA). Méthodologie: Quarante participants de plus de 50 ans ont été recrutés. De ce nombre, 14 sont des hommes et 26 sont des femmes. Ils ont consommé une dose unique de 50 mg de [indice supérieur 13] C-DHA afin de suivre son métabolisme sur une période de 28 j. L'incorporation plasmatique ainsi que la p-oxydation du [indice supérieur 13] C-DHA ont été suivis à l'aide d'échantillons de plasma et d'haleine prélevés avant la prise du [indice supérieur 13] C-DHA et 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 7 j, 14 j, 21 j et 28 j post-consommation. Résultats: 6 participants étaient porteurs de l'ApoE4 et 34 étaient non-porteurs. L'incorporation plasmatique du [indice supérieur 13] C-DHA était 3,7 fois moins grande chez les porteurs de l'ApoE4 2 h post-consommation (p = 0,04) et 1,9 fois moins grande 4 h post-consommation (p = 0,04) comparativement aux non-porteurs de l'ApoE4. La beta-oxydation du [indice supérieur 13] C-DHA était 1,8 fois plus grande chez les porteurs de l'ApoE4 7 j post-consommation (p = 0,05), 2,4 fois plus grande 21 j post-consommation (p = 0,02) et 2,3 fois plus grande 28 j post-consommation comparativement aux non- porteurs. Discussion/conclusion: Ces résultats suggèrent que les porteurs de l'ApoE4 montrent un débalancement dans leur métabolisme du [indice supérieur 13] C-DHA. Ceci pourrait modifier l'apport recommandé en DHA chez les porteurs de l'ApoE4 afin que ceux-ci soient protégés contre le déclin cognitif par la consommation d'acides gras oméga-3.