La bactérie Helicobacter pylori est responsable de l’infection la plus répandue dans la population mondiale. Cette bactérie est considérée comme le principal agent étiologique de la gastrite chronique, de l’ulcère duodénal et du cancer gastrique non-héréditaire. La thérapeutique prescrite pour l’éradication de cette infection est inefficace pour un nombre de plus en plus élevé de patients, dû à l’induction constante de souches résistantes aux antibiotiques habituellement prescrits.H. pylori a aussi d’autres façons d’assurer sa survie dans le milieu gastrique que l’induction de résistances aux antibiotiques. En particulier en intéragissant avec le cholestérol des cellules épithéliales gastriques. De ce fait, l’utilisation de molécules inhibitrices de la croissance de H. pylori, autres que les antibiotiques classiques, est une stratégie importante pour combattre cette infection.L’objectif majeur de ce travail a été de mettre en évidence de nouvelles molécules inhibitrices de la croissance et de la viabilité de H. pylori, permettant ainsi le développement de solutions alternatives à la thérapeutique classiquement utilisée. Les acides gras polyinsaturés et l’acide docosahexaenoic (DHA) se mettre en lumière pour réunir incontestable propriété anti-inflammatoires et anti-tumoral. Nous avons émis l’hypothèse que le DHA influence la survie de H. pylori, et peut moduler la disponibilité des acides gras et du cholestérol cellulaires.Nos résultats montrent que le DHA inhibe la croissance de H. pylori in vitro et affecte sa capacité à coloniser la muqueuse gastrique dans le modèle souris. Dans ces conditions, le DHA diminue la réponse inflammatoire gastrique induite par l’infection. Au niveau des cellules épithéliales gastriques, des modifications du profil des acides gras et du cholestérol avec des conséquences sur le métabolisme et la signalisation cellulaire sont observées. De plus, un traitement antibiotique classique combiné à une administration de DHA aux souris infectées diminue de façon drastique la récidive de l’infection. En conclusion, cette étude démontre un effet inhibiteur du DHA sur l’infection par H. pylori et sa récidive. Ces résultats justifient la proposition du DHA comme coadjuvant thérapeutique, constituant ainsi une stratégie prophylactique alternative de l’éradication de l’infection par H. pylori. / H. pylori infection is extremely common worldwide and is recognized as a major etiological factor in chronic active gastritis, gastric duodenal ulcers and gastric cancer development. H. pylori eradication treatment has not changed to a large extent in the last decades and can raise some concern mainly due to recurrence of infection, and most importantly, acquired resistance to classically used antibiotics. In this context, the use of compounds other than antibiotics that could decrease H. pylori infection in a safe way could provide an alternative to tackle this problem. It is known that H. pylori extracts cholesterol from host cell-membrane rafts, modifies it into an α-glycosylated form, and uses this mechanism to increase its survival. The main aim of this thesis work was to explore the role of different non-antibiotic molecules in inhibiting H. pylori growth. Among molecules known to affect in vitro H. pylori growth and viability are certain polyunsaturated fatty acids (PUFAs). Within the many molecules available, we concentrated our efforts on the study of docosahexaenoic acid (DHA). We also pursued the hypothesis that DHA affects survival of H. pylori by modulating the host epithelial cell levels of fatty acids and cholesterol availability.Our results show that DHA inhibits H. pylori growth both in vitro and in vivo, and attenuates the host inflammatory response. Additionally, we demonstrate that DHA induces morphological and cell wall protein composition changes that altogether decrease bacteria-gastric epithelial cell adherence, inflammation and survival. Also, we demonstrated that DHA alters cholesterol levels in epithelial cells, thereby influencing H. pylori ability to uptake and use epithelial cholesterol. This will ultimately impair H. pylori survival. Importantly, the combination of DHA and antibiotic standard treatment decreased the recurrence of H. pylori infection in a mouse model. Our results have gathered important evidence to pave the way for DHA use in the clinical setting and in prophylactic/preventive strategies against H. pylori infection.

L’acide docosahexaénoïque (DHA) est un acide gras polyinsaturé oméga-3 avec des propriétés anti-inflammatoires et anti-tumorales. L’effet du DHA dans le cadre du cancer colorectal pourrait être la conséquence d'une action anti-proliférative directe sur les cellules cancéreuses et de sa capacité à réduire l’inflammation propice au développement de la tumeur. Le Tumor Necrosis Factor-alpha (TNFa) est une cytokine pro-inflammatoire et présente des effets paradoxaux. En fonction du contexte cellulaire, le TNFa activera une voie de signalisation dépendante de la kinase RIP1 engageant la cellule cancéreuse vers la prolifération ou la mort cellulaire. Notre objectif fut d'évaluer le rôle du TNFa dans l'effet anti-prolifératif du DHA sur des cellules cancéreuses coliques et de préciser les mécanismes moléculaires régulant l'expression de cette cytokine. Le DHA induit l'expression de TNFa et sa sécrétion par les cellules cancéreuses. Nous avons montré que des anticorps neutralisant l'action autocrine du TNFa sur les cellules cancéreuses prévenait l'effet pro-apoptotique du DHA et abolissait l'effet anti-cancéreux observé dans des souris nude avec tumeurs HCT-116 sous régime DHA. L’induction de l'expression de TNFa par le DHA prend son origine à un niveau post-transcriptionnel par la répression du microARN miR-21 perdant sa capacité à dégrader l'ARNm TNFa. Le DHA par l'activation des kinases AMPKa et RIP1 déclenche la translocation nucléaire du facteur de transcription FOXO3a se fixant sur le promoteur miR-21 et diminuant l’expression de ce microARN. Nos travaux mettent en évidence un nouveau mécanisme moléculaire soutenant l'action anti-tumorale du DHA. / Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid with anti-inflammatory and anti-tumoral properties. The anti-tumor effect of DHA in colorectal cancer might be attributed to direct anti-proliferative action on cancer cells and to its ability to reduce inflammatory status involved in tumor growth. Tumor Necrosis Factor-alpha (TNFa) is an inflammatory cytokine with paradoxical effect in cancer biology. According to the cellular context, TNFa activates RIP1 kinase dependent signaling pathway leading to proliferation or cell death. Our aim was to evaluate the role of TNFa in anti-proliferative effect of DHA in colon cancer cells and to precise the molecular mechanisms regulating TNFa expression.DHA treatment increased TNFa expression and secretion by cancer cells. We have shown that neutralization of autocrine TNFa action prevented the pro-apoptotic effect of DHA colon cancer cells and abolished anti-cancer effect in tumor HCT-116 bearing nude mice fed a DHA-enriched diet. Induction of TNFa expression by DHA occured at post-transcriptional level through microRNA miR-21 repression reducing its ability to induce TNFa mRNA degradation. DHA activates AMPKa and RIP1 kinases triggering nuclear translocation of the transcription factor Foxo3a which bound to miR-21 promoter and repressed the microRNA expression. Our works highlight a new molecular mechanism supporting the anti-cancer action of DHA.

Made available in DSpace on 2014-07-29T15:23:45Z (GMT). No. of bitstreams: 1 DEBORA CALDAS MARQUES.pdf: 1050150 bytes, checksum: fcd394299d813475550612fa84f0fda8 (MD5) Previous issue date: 2011-06-30 / Introduction: Cancer cachexia is characterized by weight loss, immunosuppression, and is associated with a worse prognosis and quality of life. Objectives: The aim of this study was to evaluate the effects of ω-3 supplementation on nutritional and functional status and quality of life of patients with gastrointestinal cancer. Methodology: The placebo group (n = 10) received 7 caps containing 1000 mg soya oil, and the supplement group (n = 11) received 7 caps of 1000 mg fish and flaxseed oil, containing 214.3 mg of EPA and 113.5 mg of DHA, daily, for 14 days. Were assessed weight, body composition, inflammatory and immunological markers, functional status and quality of life. Results: The average weight variation of P group before and after treatment was -0.44 ± 2.7 kg and for S group was 0.07 ± 1.4 kg, with no significant differences. The average BMI of the sample was 20.5 ± 3.4 kg/m2. Significant reduction of serum total protein (p=0.005) and albumin (p=0.011) for the P group, increased levels of CRP (p=0.005), and reduction of TLC (p=0.037). An increase of serum transferrin of S group (p=0.010) and reduced levels of CRP (p=0.033) and cortisolemia (p=0.006). It was found to increase KPS (p=0.020) in group S. No differences were found for functional status, symptoms and global health. Conclusions: This study found results that support the supplementation of ω-3 in oncology. However, further investigations are necessary involvement ω-3 associated to other therapeutic strategies. / Introdução: A caquexia do câncer é caracterizada pela perda ponderal, imunossupressão, e está associada a um pior prognóstico e qualidade de vida. Objetivos: O objetivo deste estudo foi avaliar o efeito da suplementação de ω-3 sobre o estado nutricional, capacidade funcional e qualidade de vida de pacientes com câncer gastrointestinal. Metodologia: O grupo placebo (grupo P) (n=10) recebeu 7 cápsulas de 1000 mg de óleo de soja, e o grupo suplemento (grupo S) (n=11) 7 cápsulas de 1000 mg de óleo de peixe e linhaça, contendo 214,3 mg de ácido eicosapentaenóico e 113,5 mg de ácido docosahexaenóico, diariamente, por 14 dias. Foram avaliados o peso, composição corporal, marcadores inflamatórios e imunológicos, capacidade funcional e qualidade de vida. Resultados: A média de variação de peso do grupo P antes e depois do tratamento foi de -0,44 ± 2,7 kg e do grupo S foi de 0,07 ± 1,4 kg, sem diferença estatística. A média de IMC da amostra foi de 20,5 ± 3,4 kg/m2. Houve redução significativa dos níveis séricos de proteínas totais (p=0,005) e albumina (p=0,011) para o grupo P; aumento dos níveis de proteína C reativa (p=0,005), e redução da Contagem Total de Linfócitos (p=0,037). Verificou-se aumento dos níveis séricos da transferrina do grupo S (p=0,010), bem como redução dos níveis de PCR (p=0,033) e na cortisolemia (p=0,006). Encontrou-se aumento para KPS (p=0,020) no grupo S. Não foram encontradas diferenças para Status funcional, Sintomas e Saúde global. Conclusões: O presente estudo encontrou resultados que dão suporte à suplementação de ω-3 em oncologia. No entanto, são necessárias maiores investigações associando os ω-3 a outras estratégias terapêuticas.

Les sociétés économiquement développées sont confrontées à la problématique du vieillissement de leur population associée à la recrudescence des pathologies dégénératives. Parmi les manifestations du vieillissement, l'atteinte de l'appareil locomoteur (ostéoporose et sarcopénie) est considérée comme un problème majeur de santé publique. De ce fait, le développement de mesures préventives permettant de préserver la santé des séniors constitue un véritable enjeu de santé publique. La recherche scientifique fournit de nombreuses preuves concernant l'importance de l'alimentation dans la diminution ou l'exacerbation de certaines maladies. Ces observations confirment le vieux concept soutenant que l'adoption d'une alimentation équilibrée permet le maintien d'un état de santé satisfaisant, en particulier avec l'avancée en âge. A ce jour, le potentiel de l'huile d'olive, en tant que telle ou comme vecteur de nutriments lipophiles d'intérêt pour la prévention nutritionnelle de l'ostéoporose et de la sarcopénie, n'a jamais été testé. La prévalence de l'ostéoporose étant très supérieure chez la femme ménopausée qui souffre également d'une perte musculaire accélérée, cette population a été ciblée dans la présente étude. Dans une première étape, des résultats originaux ont été obtenus concernant l'effet de l'ovariectomie sur le métabolisme musculaire. Ainsi, notre travail montre qu'après ablation des ovaires, la synthèse protéique musculaire est réduite, en association avec une diminution d'un marqueur de la protéolyse de ce tissu. Pris dans son ensemble, ces résultats démontrent un ralentissement du renouvellement protéique musculaire suite à l'ovariectomie. En termes de mécanismes mis en jeu, une augmentation de l'infiltration lipidique tissulaire a été observée. En parallèle du ralentissement du renouvellement musculaire après ovariectomie, une augmentation du renouvellement osseux, classiquement décrit dans la littérature, a été mis en évidence. Dans un second temps, l'effet de l'huile d'olive et plus particulièrement des polyphénols présents dans cet aliment en association avec la vitamine D et l'acide ocosahexaénoïque et leur éventuelle synergie a été évalué à l'aide d'un modèle d'ostéoporose post-ménopausique. Des souris ovariectomisées ont été soumises à une des 4 huiles suivantes : huile de maïs, huile d'olive raffinée, huile d'olive extra vierge ou huile de poisson. Pour chaque huile, un groupe supplémentaire de souris ovariectomisées a reçu de l'huile enrichie en vitamine D. Cette étude a permis de mettre en évidence un effet protecteur de l'association de l'huile d'olive extra vierge et de la vitamine D sur la perte osseuse induite par l'ovariectomie chez la souris. En effet, l'accélération du renouvellement osseux consécutive à la carence estrogénique est freinée par cette association de nutriments, qui diminuent également l'expression des marqueurs du stress oxydant et de l'inflammation. Les résultats obtenus sont en cours de validation chez l'Homme grâce à une investigation clinique réalisée chez des femmes ménopausées. Celle-ci a été mise en place au cours de ces travaux de thèse. / Economically developed societies face the problem of an aging population combined with the increase in degenerative diseases. Among the signs of aging, musculoskeletal pathologies (osteoporosis and sarcopenia) are considered major public health problems. Therefore, the development of preventive measures to preserve seniors’ health is a real public health issue. Scientific research provides ample evidence of the importance of diet in diseases reduction or exacerbation. These observations confirm the old concept arguing that the adoption of a balanced diet helps to maintain a healthy life, especially with advancing age. To date, the potential of the olive oil, as such or as a vector of lipophilic nutrients, for the prevention of osteoporosis and sarcopenia, has never been tested. As the prevalence of osteoporosis is much higher in postmenopausal women who also suffer from an accelerated muscle mass loss, this population was targeted in this study. In a first step, original results were obtained regarding the effect of ovariectomy on muscle metabolism. Thus, our work showed that after removal of the ovaries, muscle protein synthesis was reduced in association with a decrease in the expression of a proteolysis marker of this tissue. Taken together, these results suggest a slowing down of muscle protein turnover after ovariectomy. In terms of mechanisms, an increase in lipid tissue infiltration was observed. The slowdown in muscle protein renewal after ovariectomy was associated with an increased bone turnover, classically described in the literature. In a second step, the effect of olive oil and more particularly its polyphenols in combination with vitamin D and docosahexaenoic acid and their possible synergy was assessed using a postmenopausal osteoporosis model. Ovariectomized mice were subjected to one of the following oils: corn oil, refined olive oil, extra virgin olive oil or fish oil. Four additional groups of ovariectomized mice received the oil fortified with vitamin D. This study demonstrated a protective effect of the combination of virgin olive oil and vitamin D on bone loss induced by ovariectomy in mice. Indeed, the acceleration of the bone turnover induced by the estrogen deficiency was inhibited by this combination of nutrients, which also decreased the expression of oxidative stress and inflammation markers. These results are currently being validated in a clinical investigation conducted in postmenopausal women, which has been established during this thesis work.

The effect of fish consumption on the risk of cardiovascular disease has been extensively studied. Omega-3 fatty acids present in fish, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been found to have beneficial effects through several mechanisms. In addition, selenium, an antioxidant, may be protective. Fish also represents the main human exposure source to the pollutant methylmercury (MeHg), which is associated with elevated cardiovascular risk in previous studies. The aim of this thesis was to evaluate whether MeHg is associated with the risk of myocardial infarction (MI) or stroke, whether EPA+DHA or selenium (Se) have protective associations, and if the overall association between fish consumption and risk of stroke or MI is detrimental or protective. A prospective incident case-control study design was used to study effects on stroke or MI. Three hundred and sixty-nine cases with twice as many matched controls were included in the study on stroke, while 431 cases with 499 controls participated in the MI study, all from the Northern Sweden Health and Disease Study. The data was collected from health examinations of the population from 1986 until 1999. Also, time trends in burdens of mercury (Hg), lead (Pb) and cadmium (Cd) in erythrocytes (Ery) from 1990 to 1999 were examined. The food frequency questionnaire (FFQ) used in the case-control studies was correlated with measurements of fatty acids in erythrocyte membranes as biomarkers of intake. In this northern Swedish population, levels of Ery-Hg and Ery-Pb decreased during the 1990´s, but Ery-Cd decreased only in smoking men. No significant associations were found between Ery-Hg or levels of EPA+DHA and the risk of stroke. Men reporting fish consumption >3 meals/week had an elevated risk of stroke. In the MI study, higher levels of Ery-Hg were associated with lower risk of MI. No clear associations were found for reported fish consumption, levels of EPA+DHA or Ery-Se. The validated FFQ has a fair reliability in estimating intake of fatty acids EPA and DHA. However, the low variation in fish consumption in the general population in combination with different versions of the FFQ (with pre-defined, multiple choice alternatives) decreased the reliability of self-reported fish consumption in the case-control studies on risk of stroke or MI. In conclusion, MeHg has no harmful association regarding the risk of stroke or MI in this population with generally low exposure levels. The protective association regarding risk of MI is probably due to Ery-Hg being a biomarker for consumption of fish, a source of other beneficial nutrients. Thus, in this population the benefits of the nutrients in fish appear to overcome the potential harm of MeHg. The finding of elevated stroke risk related to high fish consumption in men will be investigated further. / PHIME; Public health impact of long-term, low-level mixed element exposure in susceptible population strata

Dietary n-3 polyunsaturated fatty acids (PUFA) have been shown to potently attenuate T cell-mediated inflammation, in part, by suppressing T cell activation and proliferation. Apoptosis is an important mechanism for preventing chronic inflammation by maintaining T cell homeostasis through the contraction of populations of activated T cells. We hypothesized that dietary n-3 PUFA would promote T cell apoptosis, thus, providing an additional mechanism to explain the anti-inflammatory effects. We specifically examined activation-induced cell death (AICD) since it is the form of apoptosis associated with peripheral T cell deletion involved in immunological tolerance and T cell homeostasis. Female C57BL/6 mice were fed diets containing either n-6 PUFA (control) or n-3 PUFA for 14 d. Splenic T cells were stimulated with CD3/CD28, CD3/PMA, or PMA/Ionomycin for 48 h followed by reactivation with the same stimuli for 5 h. Apoptosis was measured using Annexin V/propidium iodide and flow cytometry. Cytokine analyses revealed that n-3 PUFA enhanced AICD only in T cells expressing a Th1-like cytokine profile (high IFN, low IL-4) compared to mice fed the n-6 PUFA control diet. Dietary n-3 PUFA significantly altered the fatty acid composition of phosphatidylcholine and phosphatidylethanolamine in T cell membranes. To examine the apparently selective effect of dietary n-3 PUFA on AICD in Th1 cells, CD4+ T cells were polarized in vitro to a Th1 phenotype by culture with IL-4, IL-2, and IL-12 for 2 d, followed by culture with IL-2 and IL-12 for 3 d in the presence of diet-matched homologous mouse serum (MS) to prevent loss of cell membrane fatty acids. Following polarization and reactivation, we observed that n-3 PUFA enhanced Th1 polarization and AICD only in cells cultured in the presence of MS, but not in fetal bovine serum. The n-3 PUFA enhancement of Th1 polarization and AICD was associated with the maintenance of diet-induced changes in EPA (20:5n-3) and DHA (22:6n-3) in plasma T cell membrane lipid rafts. Overall, these results suggest that dietary n-3 PUFA enhance both the polarization and deletion of pro-inflammatory Th1 cells, possibly as a result of alterations in lipid raft fatty acid composition.

[Formulae and special characters can only be approximated here. Please see the pdf version of the Abtract for an accurate reproduction.] Type 2 diabetes at least doubles the risk of cardiovascular disease. This can partly be explained by the increased prevalence of risk factors such as hypertension, dyslipidaemia and obesity. However, the underlying abnormality of insulin resistance and the presence of more recently identified risk factors including endothelial dysfunction, increased inflammation, and increased oxidative stress might also contribute towards the heightened cardiovascular risk. Fish oil, which contains eicosapentaenoic acid (EPA, 20:5 n-3), has wide-ranging beneficial effects on these and other abnormalities, and has reduced cardiovascular mortality in secondary prevention studies. Animal and human studies have recently established that in addition to EPA, docosahexaenoic acid (DHA, 22:6 n-3) also has beneficial effects, and furthermore, may have less detrimental effects than EPA on glycaemic control which has worsened in some fish and fish oil studies involving Type 2 diabetic subjects. Study 1 : This intervention study aimed to determine the independent effects of EPA and DHA on cardiovascular risk factors and glycaemic control in individuals with Type 2 diabetes receiving treatment for hypertension. In a double-blind placebo-controlled trial of parallel design, 59 subjects in good to moderate glycaemic control (HbA1c < 9%) were recruited from media advertising and randomised to 4 g/day of EPA, DHA or olive oil (placebo) for 6 weeks. Thirty-nine men and 12 post-menopausal women aged 61.2±1.2 yrs completed the study. Relative to placebo, and with Bonferroni adjustments for multiple comparisons, serum triglycerides fell by 19% (p=0.022) and 15% (p=0.022) in the EPA and DHA groups respectively. There were no changes in serum total cholesterol, or LDL- and HDL-cholesterol, although HDL2-cholesterol increased 16% with EPA (p=0.026) and 12% with DHA (p=0.05). HDL3-cholesterol fell by 11% (p=0.026) with EPA supplementation and LDL particle size increased by 0.26±0.10 nm (p=0.02) with DHA. Urinary F2-isoprostanes, an in-vivo marker of oxidative stress was reduced by 19% following EPA (p=0.034) and by 20% following DHA. DHA but not EPA supplementation reduced collagen-stimulated platelet aggregation (16.9%, p=0.05) and thromboxane release (18.8%, p=0.03), but there were no significant changes in PAF-stimulated platelet aggregation. Fasting glucose rose by 1.40±0.29 mmol/l (p=0.002) following EPA and 0.98±0.29 mmol/l (p=0.002) following DHA. Neither EPA nor DHA had any significant effect on HbA1c, fasting serum insulin or C-peptide, insulin sensitivity, stimulated insulin secretion, 24-hr ambulatory blood pressure and heart rate, markers of inflammation, and fibrinolytic or vascular function. Study 2 : This study aimed to examine the influence and causes of increased inflammation on vascular function in subjects recruited for Study 1. Compared with healthy controls (n=17), the diabetic subjects (n=29) had impaired flow-mediated dilatation (FMD) (3.9±3.0% vs 5.5±2.4%, p=0.07) and glyceryl-trinitrate mediated dilatation (GTNMD) (11.4±4.8% vs 15.4±7.1%, p=0.04) of the brachial artery. They also had higher levels of the inflammatory markers C-reactive protein (2.7±2.6 mg/l vs 1.4±1.1 mg/l, p=0.03), fibrinogen (3.4±0.7 g/l vs 2.7±0.3 g/l, p<0.001) and tumor necrosis factor-alpha (20.9±13.4 pg/l vs 2.5±1.7 pg/l, p<0.001). In diabetic subjects, after adjustment for age and gender, leukocyte count was an independent predictor of FMD (p=0.02), accounting for 17% of total variance. Similarly, leukocyte count accounted for 23% (p<0.001) and IL-6 for 12% (p=0.03) of variance in GTNMD. Von Willebrand factor, a marker of endothelial cell activation was correlated with leukocyte count (r=0.38, p=0.04), FMD (r=-0.35, p=0.06) and GTNMD (r=-0.47, p=0.009), whilst P-selectin, a marker of platelet activation was correlated with fibrinogen (r=0.58, p=0.001). Conclusion : EPA and DHA have similar beneficial effects on triglycerides, HDL2 cholesterol and oxidative stress in individuals with Type 2 diabetes and hypertension. However, DHA also increases LDL particle size and reduces collagen-stimulated platelet aggregation and thromboxane release, thus offering more potential than EPA as an anti-thrombotic agent. The beneficial effects of both oils were potentially offset by deterioration in glycaemic control. Neither oil affected blood pressure or vascular function. Longer-term studies with major morbidity and mortality as the primary outcome measures are required to assess the overall benefits and risks of EPA and DHA. The cross-sectional observations from Study 2 are consistent with the hypothesis that impaired vascular function in individuals with Type 2 diabetes and hypertension is at least in part secondary to increased inflammation, with associated endothelial and platelet activation.

Malgré les avancées thérapeutiques récentes, un nombre significatif de patients décèdent de leur cancer suite au développement de métastases. Les molécules conventionnelles de chimiothérapie ont un rôle pivot à ce stade, mais leur efficacité qui est dépendante de la dose, est limitée par leur toxicité aux tissus non tumoraux, par manque de spécificité. L’enjeu est de développer des approches spécifiques qui augmentent la toxicité de ces molécules pour les tumeurs sans affecter les autres tissus. L’acide docosahexaènoïque (DHA) est capable d’augmenter la sensibilité des tumeurs à la chimiothérapie de façon spécifique sans sensibiliser les tissus non tumoraux. Ce travail de thèse présente 1) une synthèse des études existantes supportant cette hypothèse, 2) l’évaluation de la faisabilité d’une supplémentation orale en DHA au cours de la chimiothérapie chez des patientes présentant un cancer du sein métastasé, 3) l’exploration des mécanismes impliqués dans la sensibilisation spécifique des tumeurs, 4) l’effet du DHA sur la perte de poids en cours de traitement, et 5) le profil d’incorporation du DHA au niveau des tumeurs et la relation avec son taux plasmatique. / Despite great therapeutic improvements, a significant proportion of patients still die from cancer, mainly because of the development of metastases. At this stage, treatments rely heavily on conventional chemotherapy, but their efficacy, which is dose-dependent, is limited by its toxicity to non-tumor tissues, as a result of their poor selectivity. The challenge is to develop approaches aimed at increasing chemotherapy cytotoxicity to tumor tissue while not affecting non-tumor tissues. Docosahexaenoic acid (DHA), a lipid of marine origin, has the potential to selectively sensitize tumor tissue to anticancer drugs without sensitizing nontumor tissues. This manuscript reports 1) a review of existing studies supporting this hypothesis, 2) an assessement of the feasiblility of supplementing breast cancer patients with DHA during an anthracycline-based chemotherapy for metastases, 3) an exploration of the mechanisms involved in the selective sensitization of tumors by DHA, 4) the effect of DHA on weight loss related to chemotherapy, and 5) the profile of DHA incorporation into tumor tissue and the relation with its level in plasma.

La composition en acides gras du tissu adipeux mammaire est reconnue comme marqueur qualitatif de la consommation lipidique antérieure mais aussi de la part nutritionnelle du risque / pronostic du cancer du sein. Ceci ouvre la perspective d’individualiser dans la population générale, un groupe de personnes à risque, susceptibles de bénéficier d’une intervention nutritionnelle ciblée. L’approche du dépistage d’une population à risque par l’utilisation de la composition du tissu adipeux comme biomarqueur se heurte i) à l’aspect invasif que représente le prélèvement d’un fragment de tissu adipeux mammaire, et ii) à la lourdeur contraignante du conditionnement et de l’analyse systématique des acides gras du tissu adipeux. Les méthodes analytiques actuellement disponibles sont incompatibles avec la perspective d’un dépistage de masse. Cependant, les descriptions récentes de l’utilisation de la spectroscopie par résonance magnétique (SRM) pour décrire la composition lipidique des triglycérides du tissu adipeux permettent d’envisager de l’utiliser dans cet objectif. Ce travail de thèse présente: 1) l’évaluation de la SRM pour caractériser la composition en acides gras du tissu adipeux chez l’animal (le rat) suite à une intervention nutritionnelle, 2) l’évaluation du profil lipidique du tissu adipeux par SRM chez la femme sur une plateforme clinique 3T, 3) l’étude des liens entre la composition en acides gras du tissu adipeux et la présentation du cancer du sein, et 4) la comparaison des données de la SRM in vitro (11.7T) et in vivo (3T) du tissu adipeux chez des patientes prises en charge pour un cancer du sein avec les données de la chromatographie gazeuse. / Fatty acid composition of the white adipose tissue remains the most reliable qualitative biomarker of previous dietary intake of fatty acids and may provide information on the nutritional part of the risk or evolution of breast cancer. This opens the prospect of individualization of women at high nutritional risk of breast cancer that may benefit from a targeted nutritional intervention but 1) the need for biopsy and 2) subsequent time-consuming biochemical analyses hamper any application of this approach. Proton magnetic resonance spectroscopy (1H-MRS) of adipose tissue lipids represents an appealing, non-invasive approach, which could circumvent these limitations. This manuscript reports: 1) an assessment of feasibility of (1H-MRS) to evaluate the consequences of a nutritional intervention in a rat mammary tumor model on the adipose tissue fatty acid composition, 2) an assessment of the feasibility of in vivo measurement of the fatty acid composition of breast adipose tissue by (1H-MRS) on a clinical platform, 3) an assessment of the relation of specific patterns of composition of adipose tissue fatty acids with the presentation of breast cancer, and 4) a comparison with gas chromatography of (1H-MRS) data acquired on breast adipose tissue in vitro (11.7T) and in vivo (3T) on patients managed for breast cancer.

The thesis deals with beneficial omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and their beneficial effects on health. Characteristics, properties and appearance of omega-3 fatty acids may explain some of the mechanisms of their effects on human health manifested not only in the treatment and mitigation of some non-infectious diseases of mass occurrence, but especially in the area of preventive action. Theoretic information used in the first part of this work was obtained from scientific and professional publications and periodicals searched in domestic and international databases of scientific and specialist literature. The part of data collection and analysis compares the intake of omega-3 acids in the form of fish dishes prepared for children in the first half of elementary school, aged 7 to 10 years, in randomly selected school canteens or contracted catering in the European Union with the recommendations of Decree 107/2005 Sb. Ministry of Education.