Orientador: Mauro Pedrine [Unesp] Santamaria / Resumo: A destruição periodontal resulta principalmente da resposta inflamatória exacerbada do hospedeiro frente ao desafio bacteriano. Por isso, pesquisas envolvendo a modulação da resposta do hospedeiro têm sido desenvolvidas com o objetivo de facilitar a resolução da inflamação, bem como promover reparação tecidual e estabilidade periodontal. Recentemente, o uso de ácidos graxos poli-insaturados de ômega-3 (AGP Ω-3) e ácido acetilsalicílico (AAS) foi relacionado à produção de mediadores lipídicos mais bioativos e à melhores resultados clínicos no tratamento de periodontite crônica. Desse modo, pesquisas envolvendo modulação das respostas inflamatórias de portadores de periodontite agressiva (PAg) podem ser de grande valia. Assim, o objetivo dos presentes estudos clínicos controlados randomizados foi avaliar a utilização da suplementação de 900 mg AGP Ω-3 e 100 mg de AAS por 180 dias como adjuvantes ao tratamento de PAg generalizada (PAgG). (1) Selecionou-se 38 pacientes com PAgG os quais receberam debridamento subgengival associado a AGP Ω-3 e AAS (n=19) ou placebo (n=19). Ambos os grupos apresentaram diminuição (p<0,05) em todos os parâmetros clínicos avaliados, bem como em IL-1β, sem diferença entre os tratamentos (p>0,05). O nível de TIMP-2 diminuiu significantemente no grupo controle, porém se manteve estável no grupo teste. Concluiu-se que a nova terapia proposta não trouxe benefícios clínicos no tratamento não-cirúrgico de PAgG. (2) Selecionou-se 34 pacientes com PAgG previa... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

Les omégas trois ont un bénéfice prouvé dans la prévention de maladie cardiovasculaire et l’inflammation. Un apport optimal peut être réalisé avec des modifications diététiques simples permettant d’avoir un enrichissement des membranes cellulaires et un effet métabolique. Le tissu adipeux de part son rôle important dans la genèse du syndrome métabolique semble être une cible importante du traitement par oméga trois. Les patients avec une maladie rénale chronique (MRC) ont un risque cardiovasculaire accru et cumulent les perturbations métaboliques comme le syndrome métabolique et un état micro inflammatoire. Des doses supra physiologiques d’oméga trois ont été utilisés dans le passé dans des études de prévention rénale ou traitement de dyslipidémie. Or l’effet métabolique en fonction de la dose d’oméga 3 n’est pas connu. En accord, avec les études chez le sujet sain, en fonction de la dose administrée, les omégas 3 ont un impact différent métabolique et sur l’expression génique. Des études complémentaires sont nécessaires pour vérifier la faisabilité et l’impact métabolique d’une modification de régime afin de diminuer le rapport n-6/n-3, ainsi que l’effet à long terme des omégas trois chez ces patients. Par ailleurs, les mécanismes impliqués dans les différences de dose réponse devront être caractérisés sur un modèle animal / Omega 3 fatty acids play an important modulatory role in metabolic and inflammatory responses, the progression of atherosclerosis and gene expression. Recent studies suggest their beneficial impact on adipocyte morphology and function. Chronic kidney disease (CKD) patients have an increased cardiovascular morbi-mortality and suffer from a cluster of metabolic disorders. On the basis of previous studies there are reasons to suggest that omega 3 supplementation may offer a host of benefits to CKD patients. Unfortunatly, published studies on the effect of such supplementation are characterized by supra physiological omega 3 doses, that may be difficult to implement for extended periods in one hand and in the other hand the metabolic effect of different doses of omega 3 hasn’t been studied in detail. Simple dietary modifications can help achieve the recommended n-6/n-3 ratio in healthy subjects. In CKD patients supplementation with n-3 shows a differential dose response effect. Further studies are required to test the faisability and metabolic impact of dietary modifications in order to decrease n-6/n-3 ratio and to assess the long term effect of omega supplementation in CKD patients. Finally the molecular pathways implicated in this differential dose response should be assessed in animal models

No description available.

Le syndrome d’apnées obstructives du sommeil (SAOS) est une pathologie caractérisée par des épisodes d’hypoxie intermittente (HI) nocturnes et est un problème de santé publique par sa prévalence dans la population générale (5-20%) et ses nombreuses complications métaboliques et cardiovasculaires. La répétition des épisodes d’HI est considérée comme le facteur principal responsable de cette morbidité cardiovasculaire dont l’athérosclérose fait partie. Le traitement de référence du SAOS par la pression positive continue présente dans certains cas une efficacité limitée, en particulier sur les conséquences cardiovasculaires qui nécessitent d’autres thérapeutiques plus spécifiques. Les mécanismes reliant SAOS et athérosclérose ne sont pas encore totalement connus. Cependant, des perturbations du métabolisme des acides gras (AG) en lien avec le processus athéromateux ont déjà été rapportées au cours du SAOS. Elles concernent en particulier le métabolisme de l’acide arachidonique (AG n-6) avec une augmentation d’eicosanoïdes pro-inflammatoires. Par ailleurs, les AG n-3 peuvent avoir une influence sur le développement et la progression des maladies cardiovasculaires, notamment grâce à une modification de la balance AG n-6 / AG n-3. Ainsi l’objectif de ce travail a donc été dans un premier temps de caractériser expérimentalement l’effet d’une supplémentation en AG n-3 sur le développement de l’athérosclérose dans le contexte d’HIC, et d’évaluer cliniquement la distribution AG n-6 / AG n-3 au niveau érythrocytaire chez des patients atteints d’un SAOS. Nous avons démontré que la supplémentation en AG n-3 permet de prévenir l’accélération de l’athérosclérose dans le contexte de l’HIC et est associée à une modulation de l’expression de certains médiateurs inflammatoires. Ces résultats prometteurs incitent à envisager une étude interventionnelle chez les patients SAOS. Dans un second temps, nous nous sommes intéressés au métabolisme des AG, via la β-oxydation mitochondriale, et aux métabolites intermédiaires produits, les acylcarnitines (ACs). Ces métabolites sont de plus en plus étudiés dans le contexte des pathologies cardiovasculaires. Nous avons étudié l’impact du SAOS sur la β-oxydation et ses conséquences sur la fonction vasculaire. L’étude de ces métabolites semble prometteuse et permettra peut-être l’émergence de marqueurs biologiques en relation avec l’état cardiovasculaire des patients. / Obstructive sleep apnea (OSA) syndrome is a disease characterized by recurrent episodes of nocturnal intermittent hypoxia (IH). OSA is a major public health problem due to its frequency in general population (5 to 20%) and its numerous metabolic and cardiovascular complications. Repetitive apneas lead to IH which is responsible of early atherosclerosis and cardiovascular complications. Gold standard treatment of OSA, that is to say continuous positive airway pressure, has poor effects on OSA cardiovascular consequences in some patients, underlining the need of alternative therapeutic strategies. Underlying mechanisms linking OSA to atherosclerosis are still poorly understood. Nevertheless, a link between polyunsaturated fatty acids (PUFAs) metabolism changes and atheromatous process has already been report during OSA syndrome. Arachidonic acid (n-6 PUFA) metabolism leads to increased biosynthesis of pro-inflammatory eicosanoids during OSA. Moreover, n-3 PUFAs influence cardiovascular complications progression especially by modifying n-6 FA / n-3 FA balance. The aim of this work was first to evaluate the influence of n-3 PUFAs supplementation on a CIH induced atherosclerosis progression model, and to clinically evaluate erythrocyte n-6 PUFA / n-3 PUFA distribution in OSA patients. We have shown that n-3 PUFAs supplementation prevents atherosclerosis acceleration in CIH exposed mice and is associated with a modulation of inflammatory mediators. These promising results encourage us to consider an interventional clinical study in OSA patients. In a second time, we have studied FA mitochondrial β-oxidation metabolism via acylcarnitines (ACs) metabolites. These ACs are increasingly studied especially in cardiovascular diseases context. OSA impact on β-oxidation metabolism and its vascular function consequences have been evaluated. ACs study is promising and will perhaps allow biological markers emergence in relation to cardiovascular pattern.

L'obésité est un facteur de risque majeur pour le développement de maladies psychiatriques, telles que le trouble dépressif majeur et la schizophrénie. Une consommation excessive de graisses saturées est bien connue pour provoquer non seulement des troubles métaboliques, mais également des comportements anormaux chez les modèles animaux et les humains. Les acides gras saturés augmentent l'inflammation dans divers tissus. Plusieurs études ont démontré que l'activation de la microglie en tant qu'acteur central de la neuroinflammation joue un rôle crucial dans l'anxiété liée à l'inflammation et les comportements dépressifs dans les cas d'obésité. En outre, il existe de plus en plus de preuves démontrant l'effet bénéfique de la supplémentation en acides gras polyinsaturés n-3 (AGPI n-3) sur les comportements cognitifs, anxieux et dépressifs. Nous avons précédemment montré que la supplémentation en AGPI n-3 via l'administration d'huile de poisson (FO) a des effets anxiolytiques sur les souris rendues obèses par une diète riche en gras saturés (SHFD). De plus, l'activation du récepteur couplé aux protéines G 120 (GPR120), un récepteur des AGPI n-3, dans le cerveau, attenue l'anxiété et les comportements dépressifs induits par la SHFD. Cependant, les mécanismes par lesquels GPR120 régule les changements induits par la SHFD dans les comportements liés à l'humeur ne sont toujours pas compris. Dans la présente étude, nous avons étudié le rôle du GPR120 dans les troubles anxieux et dépressifs reliés à la neuroinflammation. Parmi plusieurs types de cellules neurales, la microglie exprime fortement GPR120. Un agoniste de GPR120 (Compound A; CpdA) réduit la production et la libération de cytokines inflammatoires (IL-1B, IL-6, MCP1 et TNF-α) induites par les lipopolysaccharides (LPS) dans la microglie en culture. D'autre part, l'administration centrale de CpdA par injection intracérébroventriculaire (ICV) améliore le comportement anxieux et de malaise suite à l’injection de LPS systémique in vivo. De plus, l'acide eicosapentaénoique (EPA) et l'acide docosahexaénoique (DHA) sont des AGPI n-3 et des agonistes naturels du GPR120. L'EPA et le DHA suppriment l'inflammation dans un modèle de culture de microglies primaires, telle qu'évaluée par l'expression et la sécrétion de cytokines. Ces résultats suggèrent que l'activation du GPR120 contribue à l'amélioration de l'anxiété et des comportements de type dépressif liés à l'inflammation grâce à la régulation de la microglie. / Obesity is a major risk factor for the development of psychiatric diseases, such as major depressive disorder and anxiety. Excess intake of saturated fat is well known to cause not only metabolic diseases, but also abnormal behavior in humans and animal models. Saturated fatty acids enhance peripheral and central inflammation. Several studies have demonstrated that microglia activation as a central player in neuroinflammation plays a crucial role in inflammation-related anxiety and depressive-like behaviors in the case of obesity. Also, there is increasing evidence to demonstrate the beneficial effect of n-3 PUFAs supplementation on cognitive, anxiety and depressive-like behaviors. Previously, we reported that the n-3 PUFAs supplementation by the administration of fish oil (FO) has demonstrated anxiolytic effects on saturated high fat diet (SHFD)-induced obese mice and that, the activation of G-protein coupled receptor 120 (GPR120), a lipid sensor for n-3 poly-unsaturated fatty acids (n-3 PUFAs), in the brain rescued SHFD-induced anxiety and depressive-like behaviors. However, it is still unclear how GPR120 regulates SHFD-induced changes in mood-related behaviors. In the present study, we focused on the role of GPR120 on neuroinflammation in inflammation-related anxiety and depressive-like behaviors. Amongst the several types of brain cells, microglia demonstrated a high expression of GPR120. Compound A (CpdA), a selective agonist of GPR120, reduced lipopolysaccharide (LPS)-induced inflammatory cytokine (IL-1B, IL-6, MCP1, and TNF-a) expression and release in cultured microglia. Additionally, central administration of cpdA via intracerebroventricular (ICV) injection ameliorated neuroinflammation and systemic LPS injection-induced anxiety-like and sickness behavior in vivo. Furthermore, n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as natural agonists of GPR120 suppressed inflammation in primary cultured microglia as assessed by cytokine expression. These results suggest that GPR120 activation contributes to the amelioration of inflammation-related anxiety and depressive-like behaviors through the regulation of microglia.

Purpose: To 1) critically appraise available randomized controlled trials (RTCs) addressing the efficacy of long-chain ω-3 fatty acids as a secondary prevention agent of hypertriglyceridemia, and 2) make recommendations for clinical practice. Data Sources: All RCTs identified from several databases from 1993-2003 were reviewed by two independent reviewers who extracted data from each study and used the previously tested Boyack and Lookinland Methodological Quality Index (MQI) to determine study quality. Results: Ten studies reported long-chain ω-3 fatty acids to be effective in the treatment of hypertriglyceridemia. The average decrease in triglycerides (TG) was 29%, total cholesterol (TC) 11.6%, very low density lipoprotein (VLDL) 30.2%, and low-density lipoprotein (LDL) 32.5%. One study found LDLs to increase by 25%. The average increase in high-density lipoprotein (HDL) was 10%. The overall average MQI score was 36% (26%-54%). Many of the RCTs had serious shortcomings including short duration, lack of a power analysis, no intention to treat analysis, no report of blind assessment of outcome, and lack of dietary control as a confounding variable. Conclusions/Implications: Overall study methodology was weak. Although the evidence supporting the use of long-chain ω-3 fatty acids in the secondary prevention of hypertriglyceridemia is reasonably strong, until there are larger RCTs of stronger methodological quality, it is not recommended to treat hypertriglyceridemia with ω-3 fatty acid supplementation in lieu of lipid lowering medications.

Dietary N-3 PUFA plays a key role in brain maturation, development, stress response and cognitive abilities (Weiser et al., 2016; Devarshi et al., 2019). As adolescent’s prefrontal cortex is maturating, the period becomes sensitive to external factors such as environment, nutrition, and stress (Petrovich et al., 2001; Calabro et al., 2020). In this thesis, we aim to expand our knowledge of the influence of external factors, such as dietary omega-3 supplementation and enriched environment, during this critical maturation period. By designing four distinct studies, we tested the hypothesis that visible sex-specific alterations would arise from adolescence targeted diet n-3 PUFA supplementation and enriched environment, which would act to modify physiological and stress responses, as well as socio-emotional and cognitive performance. Our first study characterized the impact n-3 PUFA and n-6 PUFA regimen on corticosterone secretion and behavioural responses in adolescent male rodents. Additionally, it assessed the effects of delivery method (gavage versus restricted feeding) during this sensitive maturation period to ensure using a method with limited stress-mediated outcomes. This study highlighted gavage to induce reduced effects on corticosterone (CORT) secretion, regardless of the provided supplementation. On the last day of feeding, CORT secretion was diminished in fish oil (FO) fed rats exposed to restricted feeding, suggesting FO diet to promote physiological adjustments. Data also demonstrated that FO and soybean (CSO) rich diets were able to reduce anxiety-like behaviour compared to a high-fat diet intake (Hydrogenated Vegetal Fat - HVF), highlighting the role of n-3 PUFA dietary supplementation during adolescence on stress regulation. Our second study assessed sex-specific impact of adolescence targeted dietary supplementation on brain Docosahexaenoic Acid (DHA), Arachidonic Acid (AA) and Linolenic acid (LA) concentrations immediately following supplementation and during adulthood. Our findings demonstrated overall elevated DHA, AA and LA brain tissue concentrations in female compared to male rats, regardless of dietary supplementation. Benefit of supplementation were most apparent in adolescent males, where FO led to higher DHA concentrations compared to soybean oil supplementation, supporting a positive influence of FO dietary supplementation in males during intensive hormonal fluctuation and brain maturation. However, adolescent male rats showed reduced ability to extract nutrient essential fatty acids compared to female counterparts. Our third study characterized sex-specific coping strategies, socioemotional responses, and glucocorticoid regulation following an n-3 PUFA rich diet and enriched environment (EE) during the adolescent period. While basal CORT secretions were not significantly altered by supplementation in males, a gradual increase in CORT was observed during supplementation, peaking at DAY21. Passive coping strategies was preferred in the FST in RC (Regular Cage)- housed females exposed to FO while RC-housed CSO-fed males opted for an active climbing coping strategy. Increase locomotion and anxiolytic behaviour were observed in CSO-supplemented males (exposed to EE), while CSO by itself promoted social recognition in males. In contrast, sociability was improved in FO EE exposed females, indicating possible synergic effects. Adulthood hippocampal GR-ir expression was reduced at the hippocampal CA3 region in FO/RC and CSO/EE rat groups, which could have influenced memory consolidation and stress resilience. Overall, results from this study provided insights on positive effects associated with short-term adolescent n-3 PUFA supplementation in females, while male appeared to most benefited from soybean diet supplementation. Our fourth and last study assessed age- and sex-dependent influences of dietary supplementation on cognitive performance in the Barnes Maze Test. Our results showcase a gradual decrease in latencies to the escape box, as well as progressive decrease in working memory errors (WME) in adult compared to adolescent rats. Over the testing period, the FO females and CSO males showed improved performance through reduction of WMEs on specific days, which could subtend sex-related effects of dietary supplementations. However, while discrete effects of n-3 PUFA were more apparent in female rats, short-term supplementation appeared insufficient to promote consistent enhancement of visuospatial performance or cognitive flexibility that could be observed throughout the testing period. In conclusion, our findings support the importance of studying single and combined factors to understand overall impact. We were able to consistently demonstrate beneficial effects on coping strategies, stress reactivity, sociability, and cognitive performance of adolescence-targeted fish oil supplementation, especially in female rodents.

Background. Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) may have different effects on cognitive health due to their anti- or pro-inflammatory properties. Methods. We aimed to prospectively examine the relationships between n-3 and n-6 PUFA contents in serum phospholipids with incident all-cause dementia and Alzheimer’s disease dementia (AD). We included 1264 non-demented participants aged 84 ± 3 years from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) multicenter-cohort study. We investigated whether fatty acid concentrations in serum phospholipids, especially eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA), were associated with risk of incident all-cause dementia and AD. Results. During the follow-up window of seven years, 233 participants developed dementia. Higher concentrations of EPA were associated with a lower incidence of AD (hazard ratio (HR) 0.76 (95% CI 0.63; 0.93)). We also observed that higher concentrations of EPA were associated with a decreased risk for all-cause dementia (HR 0.76 (95% CI 0.61; 0.94)) and AD (HR 0.66 (95% CI 0.51; 0.85)) among apolipoprotein E ε4 (APOE ε4) non-carriers but not among APOE ε4 carriers. No other fatty acids were significantly associated with AD or dementia. Conclusions. Higher concentrations of EPA were associated with a lower risk of incident AD. This further supports a beneficial role of n-3 PUFAs for cognitive health in old age.

The American Heart Association (AHA) recently confirmed common recommendations of one to two fish dishes per week in order to prevent cardiovascular disease (CVD). Nevertheless, the natural fluctuations of lipids and fatty acids (FA) in processed seafood caught little public attention. Moreover, consumers of unprocessed seafood in general do not know how much omega-3 fatty acids (omega-3 FA) within servings they actually ingest. The few studies published until today considering this aspect have been re-evaluated in today’s context. They included four observational studies with canned fatty coldwater fish (mackerel and herring from the same region, season, producer and research group). Their outcomes were similar to those conducted in the following years using supplements. Cans containing seafood (especially fatty coldwater fish) with declared content of omega-3 FA are ready-to-use products. Human studies have shown a higher bioavailability of omega-3 FA by joint uptake of fat. Canned fatty coldwater fish contain omega-3 FA plus plenty of fat in one and the same foodstuff. That suggests a new dietary paradigm with mixed concepts including several sources with declared content of omega-3 FA for reducing the cardiovascular risk and other acknowledged indications.

No description available.