Atualmente, a demanda por alimentos com apelo funcional tem se tornado cada vez mais recorrente dentre os consumidores devido a uma crescente busca por hábitos de vida mais saudáveis. Sendo assim, o desenvolvimento de técnicas que possibilitem uma adição mais efetiva de ingredientes funcionais em matrizes alimentícias se torna uma necessidade. Essas técnicas devem possibilitar principalmente (i) a incorporação de mecanismos de liberação sustentada na formulação; (ii) o aumento da bioacessibilidade e biodisponibilidade aos ingredientes, a partir do controle da microestrutura do alimento. Esse projeto visa contemplar essas duas premissas, ao propor a encapsulação de dois bioativos hidrofóbicos, a curcumina e a vitamina D3, conhecidos pelas suas propriedades antioxidantes e nutracêuticas, em carreadores de origem lipídica, os lipossomas, estabilizando-os com diferentes hidrocoloides - goma xantana, goma guar e inulina. Os lipossomas foram produzidos por hidratação de prolipossomas e suas propriedades físico-químicas foram caracterizadas ao longo de 42 dias de armazenagem, a partir de análises de diâmetro médio hidrodinâmico, potencial zeta, colorimetria instrumental e quantificação de bioativos encapsulados. Análises que permitiram a caracterização da microestrutura das dispersões produzidas também foram realizadas, sendo elas: calorimetria diferencial de varredura (DSC), espalhamento de raios-X a baixos ângulos (SAXS) e ensaios reológicos. As análises de SAXS mostraram que lipossomas produzidos na presença de curcumina são mais estáveis que àqueles produzidos na ausência da mesma e que não houve mudança na estrutura da bicamada lipídica das vesículas após a adição de vitamina D3, mesmo quando uma alta concentração foi incorporada ao sistema (80.000 UI). Por fim, verificou-se que a coencapsulação foi possível em lipossomas multilamelares estabilizados apenas com gomas guar e xantana, resultado que pode ser comprovado pelo alto teor de retenção dos bioativos ao longo do tempo de armazenagem. / Currently, the demand for food with functional appeal has become increasingly recurrent among the consumers due to a growing search for healthier living habits. Therefore, the development of techniques that allow a more effective addition of functional ingredients in food matrices becomes a necessity. These techniques should mainly enable to (i) incorporate a sustained release mechanisms into the formulation; (ii) increase the bioaccessibility and bioavailability to these ingredients, from the control of the food microstructure. This project aims to contemplate these two premises by proposing the encapsulation of two hydrophobic bioactives, curcumin and vitamin D3, known for their antioxidant and nutraceutical properties, in liposomes - lipid carriers - stabilizing them with different hydrocolloids - xanthan gum, guar gum and inulin. Liposomes were produced by proliposomes hydration and their physicochemical properties were characterized during 42 days of storage, including analyzes of hydrodynamic average diameter, zeta potential, instrumental colorimetry and quantification of encapsulated bioactives. Analyzes that allowed the microstructure characterization of the produced dispersions were also performed, including: differential scanning calorimetry (DSC), small-angle X-ray scattering and rheological tests. The SAXS analysis showed that liposomes produced in the presence of curcumin were more stable when compared to the empty ones and that there was no change in the lipid bilayer of the vesicles after the addition of vitamin D3, even when a high concentration was incorporated into the system (80,000 IU). Finally, it was concluded that the coencapsulation was possible in multilamellar liposomes stabilized with guar and xanthan gums, a result that can be evidenced by the high content of bioactives retained throughout the storage time.

Atualmente, a demanda por alimentos com apelo funcional tem se tornado cada vez mais recorrente dentre os consumidores devido a uma crescente busca por hábitos de vida mais saudáveis. Sendo assim, o desenvolvimento de técnicas que possibilitem uma adição mais efetiva de ingredientes funcionais em matrizes alimentícias se torna uma necessidade. Essas técnicas devem possibilitar principalmente (i) a incorporação de mecanismos de liberação sustentada na formulação; (ii) o aumento da bioacessibilidade e biodisponibilidade aos ingredientes, a partir do controle da microestrutura do alimento. Esse projeto visa contemplar essas duas premissas, ao propor a encapsulação de dois bioativos hidrofóbicos, a curcumina e a vitamina D3, conhecidos pelas suas propriedades antioxidantes e nutracêuticas, em carreadores de origem lipídica, os lipossomas, estabilizando-os com diferentes hidrocoloides - goma xantana, goma guar e inulina. Os lipossomas foram produzidos por hidratação de prolipossomas e suas propriedades físico-químicas foram caracterizadas ao longo de 42 dias de armazenagem, a partir de análises de diâmetro médio hidrodinâmico, potencial zeta, colorimetria instrumental e quantificação de bioativos encapsulados. Análises que permitiram a caracterização da microestrutura das dispersões produzidas também foram realizadas, sendo elas: calorimetria diferencial de varredura (DSC), espalhamento de raios-X a baixos ângulos (SAXS) e ensaios reológicos. As análises de SAXS mostraram que lipossomas produzidos na presença de curcumina são mais estáveis que àqueles produzidos na ausência da mesma e que não houve mudança na estrutura da bicamada lipídica das vesículas após a adição de vitamina D3, mesmo quando uma alta concentração foi incorporada ao sistema (80.000 UI). Por fim, verificou-se que a coencapsulação foi possível em lipossomas multilamelares estabilizados apenas com gomas guar e xantana, resultado que pode ser comprovado pelo alto teor de retenção dos bioativos ao longo do tempo de armazenagem. / Currently, the demand for food with functional appeal has become increasingly recurrent among the consumers due to a growing search for healthier living habits. Therefore, the development of techniques that allow a more effective addition of functional ingredients in food matrices becomes a necessity. These techniques should mainly enable to (i) incorporate a sustained release mechanisms into the formulation; (ii) increase the bioaccessibility and bioavailability to these ingredients, from the control of the food microstructure. This project aims to contemplate these two premises by proposing the encapsulation of two hydrophobic bioactives, curcumin and vitamin D3, known for their antioxidant and nutraceutical properties, in liposomes - lipid carriers - stabilizing them with different hydrocolloids - xanthan gum, guar gum and inulin. Liposomes were produced by proliposomes hydration and their physicochemical properties were characterized during 42 days of storage, including analyzes of hydrodynamic average diameter, zeta potential, instrumental colorimetry and quantification of encapsulated bioactives. Analyzes that allowed the microstructure characterization of the produced dispersions were also performed, including: differential scanning calorimetry (DSC), small-angle X-ray scattering and rheological tests. The SAXS analysis showed that liposomes produced in the presence of curcumin were more stable when compared to the empty ones and that there was no change in the lipid bilayer of the vesicles after the addition of vitamin D3, even when a high concentration was incorporated into the system (80,000 IU). Finally, it was concluded that the coencapsulation was possible in multilamellar liposomes stabilized with guar and xanthan gums, a result that can be evidenced by the high content of bioactives retained throughout the storage time.

Les antipsychotiques sont des agents psychoactifs utilisés pour traiter les symptômes de la schizophrénie. Si la mise sur le marché de la seconde génération de molécule a permis de diminuer l’apparition des troubles extrapyramidaux, elle reste néanmoins associée à des effets secondaires caractérisés principalement par une prise de poids assortie d’une dyslipidémie et d'un développement du diabète de type 2. Ces effets indésirables entraînent chez les patients une dégradation de leurs conditions de vie et constituent l'une des principales causes d'abandon de ce traitement, les exposant à un risque accru de rechute. L’objectif de ce travail était double : (i) caractériser les troubles métaboliques induits par un traitement à long terme à la rispéridone en utilisant des techniques non-invasives de résonance magnétique ; (ii) prévenir ces troubles par un régime alimentaire supplémenté en curcuminoïdes. Notre modèle a permis de montrer qu'un traitement hebdomadaire de 24 semaines entraînait des perturbations apparentées au syndrome métabolique. L’imagerie par résonance magnétique était suffisamment sensible pour caractériser ces conséquences métaboliques iatrogènes et permettait de définir des biomarqueurs prédictifs de sévérité comme le ratio hydro-lipidique, le degré d’insaturation des acides gras et le remodelage de la répartition des tissus adipeux. Sur le plan pharmacologique, la supplémentation en curcuminoïdes permettait de prévenir l’hépatomégalie et l’intolérance au glucose induite par la rispéridone. Ces bénéfices étaient associés à une modulation de l’expression de gènes hépatiques impliqués dans la lipogenèse (FAS, ACC1), dans la lipolyse (ACO) ou bien dans l’inflammation (NFκB). Le cadre expérimental défini dans ce travail met en avant la possibilité de transférer cette approche prédictive par résonance magnétique en clinique humaine. / Antipsychotics are widely used psychoactive drugs for the treatment of schizophrenia symptoms. The use of second-generation agents has reduced the onset of extrapyramidal disorders, but still causes side effects comprising weight gain, dyslipidemia, and type-2 diabetes. The ensuing deterioration of patients’ conditions is one of the main reasons for the abandonment of this treatment exposing patients to an increased risk of relapse. This PhD had two objectives: (i) to characterize the metabolic disorders generated by a long-term treatment with risperidone, through the use of non-invasive techniques of magnetic resonance (MR); (ii) to prevent these disorders by means of a curcuminoid-supplemented diet. Our murine model enabled us to show that a 24-week treatment including weekly given risperidone induced metabolic disturbances related to the Metabolic Syndrome. Magnetic resonance imaging was sensitive enough to highlight these disturbances and to allow the identification of predictive biomarkers for severity such as the hydrolipidic ratio, fatty acid unsaturation rate, and adipose tissues repartitioning. At the pharmacological level, curcuminoid supplementation prevented the risperidone-induced hepatomegaly and glucose intolerance. These benefits were associated with the modulation of gene expression related to lipogenesis (FAS, ACC1), lipolysis (ACO) or inflammation (NFκB). In a clinical perspective, the herein PhD underlines the diagnostic potential of this MR-based experimental framework for the monitoring of metabolic disturbances.

Introduktion: Knäartros är en degenerativ och låggradig inflammationssjukdom, som ungefär 22,9 % av alla över 40 år lider av. Det drabbar oftare kvinnor än män, och risken ökar vid bland annat fetma samt tidigare ledskador. Vid artros sker en skada på osteoblaster, kondrocyter och synoviocyter som stimulerar frisättning av tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) samt matrixnedbrytande enzymer. Detta resulterar i smärta, ledsvullnad och degenerering av leden. Diagnos ställs genom klinisk undersökning med hjälp av exempelvis American College of Rheumatology (ACR)-kriterier. Detta kompletteras ofta med radiologisk undersökning och ibland används ett självskattningsformulär som exempelvis Western Ontario and McMaster Universities Arthritis Index (WOMAC). I WOMAC innebär en minskning av värdet en förbättring av den kliniska parametern. Artros behandlas till en början med non-steroidal anti-inflammatory drugs (NSAID)-preparat och paracetamol, mot inflammation och smärta. Curcuma longa (C. longa) även kallat gurkmeja har använts vid matlagning och traditionell medicin i nära 2500 år. Den mest aktiva enheten i C. longa är polyfenolen curcumin som utvinns från dess rhizomer. Den har visat sig vara bland annat anti-inflammatorisk och antioxidantisk, båda dessa egenskaper är viktiga vid behandling av knäartros. Curcumins biotillgänglighet är låg, men det utförs och har utförts studier för att finna formuleringar som höjer biotillgängligheten. På så vis kan effekten förbättras. Verkningsmekanismen för curcumin är inte helt klarlagd men tidigare studier tyder på att den exempelvis kan minska oxidativ stress och minska koncentrationerna av inflammatoriska biomarkörer som TNF-α, IL-1β och IL-6. Syfte: Om curcumin kan användas som ett substitut till standardbehandlingen med NSAID-preparat och paracetamol som inflammationshämmande och smärtlindrande, vid behandling av knäartros. Metod: Detta examensarbete är en litteraturstudie, sökningarna utfördes i databasen PubMed och Linnéuniversitetets Onesearch. Totalt valdes fem studier ut med kriterierna att studien skulle vara max 10 år, vara en klinisk studie samt att den primära utfallsvariabeln skulle involvera förändringar i WOMAC. Resultat: I fyra av studierna blev resultatet en statistisk signifikant minskning i kategorin WOMAC-fysisk funktion. I tre av studierna blev det en statistiskt signifikant minskning i WOMAC-smärta och i två av studierna blev det en statistiskt signifikant minskning i WOMAC-stelhet. I tre av studier minskade användningen av akutläkemedel i form av NSAID eller paracetamol varav en studie hade en statistiskt signifikant minskning jämfört med kontrollgruppen. Slutsats: Resultaten tyder på att curcumin kan vara effektiv som behandling vid knäartros. Den har visat sig ha både anti-inflammatoriska egenskaper och en smärtstillande effektt vilket tyder på att det skulle kunna vara möjligt att använda som substitut till NSAID och paracetamol. För att kunna fastställa att curcumin är en säker och effektiv behandling finns ett behov av fler och större studier.

Une nouvelle famille de complexes de difluorure de bore photosensibles est développée. Elle est basée sur des structures moléculaires contenant une unité β-dicétone à conjugaison électronique π.La grande variété de groupements aromatiques et la nature donneur ou accepteur d'électrons des différents substituants permet l'élaboration de systèmes électroniques donneur-accepteur-donneur d'électrons (D1-A-D1) et donneur-accepteur (D2-A).L'absorption électronique de cette famille de molécule se situe dans la partie visible du spectre électromagnétique et une partie du spectre ultraviolet, et est caractérisée par une bande d'absorption π-π* intense avec des coefficients d'absorption molaire supérieurs à 50 000 M-1cm-1.L'émission de fluorescence couvre une plage spectrale qui va du visible au proche infrarouge avec des rendements quantiques de fluorescence en solution relativement élevés pouvant atteindre 62 %.En fin, cette famille de molécule est photochimiquement stable et est, contrairement à d'autres familles de complexes de difluorure de bore, chimiquement très stable en solution.Mots-clés : Difluorure de bore, β-dicétone, matériaux π-conjugués, luminescence, fluorescence stationnaire et résolue dans le temps (TRES), synthèse organique, RMN-19F dynamique, complexes & colorants fluorescents, curcumine & curcuminoide, complexe BF2, photophysique. / A new photosensitive family of boron difluoride complex is developed. It is based on π-conjugated molecular structures containing β-diketonates unit.The wide variety of aromatic groups and the nature of donor or electron acceptor of the different substituents allow the development of electron donor-acceptor-donor (DAD) and donor-acceptor (DA) electronic systems.The electronic absorption of this family of molecules is in the visible part of the electromagnetic spectrum and a portion of the ultraviolet spectrum, and is characterized by an intense π-π* absorption band with molar absorption coefficient greater than 50 000 M-1.cm-1.The fluorescence emission covers a spectral range going from visible to near infrared, with relatively high fluorescence quantum yields of up to 62 % in solution.This new material family is photochemically stable and, unlike some other families of boron difluoride complexes, chemically very stable in solution.