CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O diabetes mellitus tipo 2 (DM2), doenÃa multifatorial, heterogÃnica, resulta de suscetibilidade genÃtica associada a fatores ambientais, especialmente sedentarismo e dieta rica em gorduras saturadas, e a obesidade. Caracteriza-se por resistÃncia à insulina (RI) e pela diminuiÃÃo da secreÃÃo desse hormÃnio. InflamaÃÃo moderada e crÃnica no tecido adiposo branco disfuncional, denominada âmeta-inflamaÃÃoâ, parece ser o elo entre obesidade, RI e DM2. Papel de adipocinas produzidas pelo tecido adiposo nessas afecÃÃes vem sendo investigado. Objetiva-se neste estudo verificar se suplementaÃÃo oral (SO) de mistura de Ãleos (MXO) com relaÃÃo de Ãmega 9 / Ãmega 6 (ω9/ω6) elevada e de Ãmega 6 / Ãmega 3 (ω6/ω3) baixa, de diferentes fontes de ω3, interfere em adipocinas plasmÃticas de camundongos com DM2. Depois de alimentados ad libitum com dieta da AIN-93G atà ficarem adultos, camundongos Swiss (CSW) machos receberam, por onze semanas, dieta AIN-93HA, hiperlipÃdica adaptada, para induÃÃo de DM2, confirmado em 90% deles. Mantida a dieta AIN-93HA, os CSW com DM2 receberam, em grupos, por sete dias, SO com MXO: GA: H₂O (controle nulo); GB: MXO [ω9:ω3 0,4:1;ω6:ω3 8:1 (controle neutro)]; GC: MXO [ω9:ω3 3,7:1; ω6:ω3-ALA 1,4:1]; GD: MXO [ω9:ω3 3,7:1;ω6:ω3-EPA+DHA de peixe 1,4:1]; GE: MXO [ω9:ω3 3,7:1; ω6:ω3-DHA de algas 1,4:1]. Por imunoensaios, realizou-se dosagem plasmÃtica de insulina e de adipocinas, fator de necrose tumoralâalfa (TNF-α); interleucina-6 (IL-6); interleucina-1 beta (IL-1β); fator ativador de monÃcitos (MCP-1); resistina (RES); leptina (LEP); inibidor do fator ativador de plasminogÃnio 1 (PAI-1) e adiponectina (AdipoQ). Constatou-se diferenÃa estatÃstica significante de adipocinas do grupo GE (ω3-DHA de algas), em relaÃÃo aos outros grupos, com aumento de IL-6 em relaÃÃo ao GC e GD; diminuiÃÃo de LEP em relaÃÃo ao GA; aumento de TNF-α em relaÃÃo aos grupos GB, GC e GD; e diminuiÃÃo de AdipoQ em relaÃÃo ao GB; assim como de RES entre os grupos GC (ω3-ALA) e GD (ω3-EPA+DHA). NÃo houve diferenÃa estatÃstica significante em nenhuma das variÃveis entre grupos controles. Continuidade de dieta rica em gordura saturada pode ter comprometido a eficÃcia da suplementaÃÃo de MXO ricos em ω3 e ω9. O âestado da arteâ demanda outros estudos para esclarecer o papel do DHA na âmeta-inflamaÃÃoâ. / Diabetes mellitus type 2 (DM2), a multifactorial disease, heterogenic results of associated genetic susceptibility to environmental factors, especially sedentary lifestyle and a diet rich in saturated fats, and obesity. It is characterized by insulin resistance (IR) and by decreasing the secretion of this hormone. Moderate and chronic inflammation in white adipose tissue dysfunctional, called "meta-inflammation," seems to be the link between obesity, IR and DM2. Role of adipokines produced by adipose tissue in these diseases has been investigated. Objective of this study was to verify whether oral supplementation (SO) of oil blend (MXO) compared with omega 9 / omega 6 (ω9/ω6) and high omega 6 / omega 3 (ω6/ω3) low, from different sources of ω3 interferes with adipokines plasma of mice with T2DM. After fed ad libitum with AIN-93G diet until they become adult Swiss mice (CSW) males received by eleven weeks AIN-93HA, hyperlipidic adapted to induce DM2 confirmed in 90% of them. Maintained the AIN-93HA, the CSW with T2DM were in groups of seven days, with MXO SO: GA: H ₂ O (null control) GB: MXO [ω9: ω3 0.4:1; ω6: ω3 8: 1 (neutral control)]; GC: MXO [ω9: 3.7:1 ω3, ω6: ω3-ALA 1.4:1]; GD: MXO [ω9: 3.7:1 ω3, ω6: ω3-EPA + DHA from fish 1.4:1]; GE: MXO [ω9: ω3 3.7:1; ω6: ω3, DHA from algae 1.4:1]. Why immunoassays, held measurement of plasma insulin and adipokines, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), monocyte activating factor ( MCP-1), resistin (RES), leptin (LEP), an inhibitor of plasminogen activator 1 (PAI-1) and adiponectin (ADIPOQ). It found a statistically significant difference of adipokines group GE (ω3-DHA from algae), compared to the other groups, with increased IL-6 compared to GC and GD, fewer LEP compared to GA; increase of TNF- α in relation to groups GB, GC and GD, and ADIPOQ decrease compared to GB, as well as RES between GC (ω3-ALA) and GD (ω3-EPA + DHA). There was no statistically significant difference in any of the variables between control groups. Continuity diet high in saturated fat may have compromised the effectiveness of supplementation MXO rich in ω3 and ω9. The "state of the art" demand further studies to clarify the role of DHA in the "meta-inflamaÃÃoDM2, Adipokines, saturated fatty acids, omega fatty acids 3, 6 and 9 and" meta-inflammation

<p>Cilj istraživanja u okviru ove doktorske disertacije bio je da se ispita uticaj ekstrudiranja na funkcionalno hranivo, čija bi osnovna uloga bila povećanje sadržaja omega-masnih kiselina u ishrani životinja, a naročito &alpha;-linolenske kiseline (ALA). Za proizvodnju funkcionalnog hraniva upotrebljeni su laneno seme, kao nosilac funkcionalnih osobina i suncokretova sačma, koja je dodata da se spreči isticanje lanenog ulja tokom ekstrudiranja. Nezavisni parametri ekstrudiranja čiji je uticaj ispitivan bili su: brzina obrtanja puža ekstrudera (240, 360 i 590 o/min), kapacitet punjenja (16, 24 i 32 kg/h), vlaga polaznog materijala (7, 11,5 i 16 %) i ukupna povr&scaron;ina otvora na matrici (19,8, 39,6 i 59,4 mm2). Zavisno promenljive karakteristike (odzivi) dobijenog hraniva koje su praćene bile su: sadržaj HCN u hranivu, sadržaj ALA, sadržaj slobodnih masnih kiselina (SMK) i potro&scaron;nja energije.<br />Za modelovanje zavisnosti karakteristika hraniva od procesnih parametara ekstrudiranja primenjena je metoda odzivne povr&scaron;ine (RSM), a kori&scaron;ćen je Box-Behnken-ov dizajn (BBD) za četiri faktora na tri nivoa. Za svaki od pomenutih odziva definisan je polinom drugog reda i određeni su koeficijenti polinoma, a analizom varijanse potvrđena je tačnost ovih modela. Formirani modeli upotrebljeni su za optimizaciju procesa ekstrudiranja, sa ciljem da se postigne &scaron;to veća redukcija<br />cijanogenih glikozida u hranivu, uz &scaron;to vi&scaron;i sadržaj ALA i &scaron;to niže SMK i potro&scaron;nju energije. Da bi se zadovoljili svi postavljeni uslovi optimizacije, proces ekstrudiranja bilo je potrebno izvoditi pod sledećim uslovima: brzina obrtanja puža &ndash; 417,41 o/min, kapacitet punjenja &ndash; 32 kg/h, vlaga materijala &ndash; 13,39 % i ukupna povr&scaron;ina otvora na<br />matrici &ndash; 19,80 mm2.<br />Ovako dobijeno hranivo pokazalo je nizak sadržaj HCN, čiji je stepen redukcije u odnosu na početnu vrednost iznosio 76,20 %. Sa druge strane, sadržaj ALA smanjen je za svega 0,69 %, &scaron;to ukazuje da ekstrudiranje nije negativno uticalo na masnokiselinski sastav proizvedenog ko-ekstrudata.<br />Nakon proizvodnje ko-ekstrudata, pristupilo se ispitivanju njegove održivosti. U tu svrhu uzorci su skladi&scaron;teni u klima komori sa mogućno&scaron;ću kontrolisanog pode&scaron;avanja temperature, relativne vlažnosti i cirkulacije vazduha. Za praćenje održivosti proizvoda primenjen je modifikovan Schaal-oven test. Modifikacija metode sastojala se u pode&scaron;avanju relativne vlažnosti vazduha na konstantnu vrednost od 40 %, &scaron;to klasičnom metodom nije propisano. Ova vlažnost vazduha odabrana je na osnovu relativne vlažnosti koja je u trenutku eksperimenta izmerena u prostoriji. U cilju ispitivanja uticaja antioksidanasa na oksidativnu stabilnost proizvoda, uzorcima su dodavani komercijalni preparati karvakrol (200 mg/100 g koekstrudata), vitamin E (135 mg/100 g ko-ekstrudata) i sme&scaron;a ova dva antioksidansa. Za praćenje oksidativnih i hemijskih promena ko-ekstrudata, određivani su peroksidni broj (Pbr), SMK uzorcima su dodavani komercijalni preparati karvakrol (200 mg/100 g koekstrudata), vitamin E (135 mg/100 g i masnokiselinski sastav. Takođe su ispitane mikrobiolo&scaron;ke promene u koekstrudatu. Najsnažnije antioksidativno dejstvo u ovom eksperimentu imao je vitamin E, dok sme&scaron;a vitamina E i karvakrola nije pokazala sinergističko dejstvo. Sastav masnih kiselina se u toku skladi&scaron;tenja nije statistički značajno promenio. Sa druge strane, ekstrudiranje je pokazalo statistički značajan uticaj (p = 0,032) na redukciju ukupnog broja mikroorganizama u hranivu, a najniža vrednost ukupnog broja mikroorganizama (600 cfu/g) zabeležena je u uzorku sa dodatim karvakrolom.</p> / <p>The goal of the research in this thesis was to examine the effect of extrusion on functional feed compound, whose main role was to increase the content of omega-fatty acids in animal nutrition, especially &alpha;-linolenic acid (ALA). Flax seed, as the holder of the functional properties, and sunflower meal, as an adsorbent of linseed oil during extrusion, were used for the production of functional feed compound. Independent extrusion parameters studied in the experiment were: extruder screw speed (240, 360 and 590 rpm), loading capacity (16, 24 and 32 kg/h), the moisture content of the starting material (7, 11.5 and 16 % ) and the total die opening&rsquo;s area (19.8, 39.6 and 59.4 mm2). Dependent variables (responses) of the produced feed compound were: HCN content in coextrudate, ALA content, the content of free fatty acids (FFA) and energy consumption.<br />Response surface methodology (RSM) was applied in order to model mathematical dependence between co-extrudate characteristics and the independent process parameters. The experiments were designed according to Box-Behnken&#39;s design (BBD) with four factors, each at three levels. Second-order polynomial equation was<br />developed for each of these responses, and polynomial coefficients were determined. Accuracy of each model was confirmed by analysis of variance (ANOVA). Formed polynomial models were used to optimize the extrusion process, with the aim of achieving high reduction of cyanogenic glycosides in feed compound, the highest content of ALA, as well as low FFA and low energy consumption. Obtained optimal conditions were: extruder srew speed - 417.41 rpm, loading capacity - 32 kg/h, moisture content of starting material - 13.39 % and the total die openings&rsquo; area<br />- 19.80 mm2.<br />Functional feed compound produced under these conditions showed a low concentration of HCN, and the degree of HCN reduction was 76.20 % compared to the starting HCN content. On the other hand, the ALA content was reduced by only 0.69 %, indicating that extrusion did not significantly affect the fatty acid composition of the produced co-extrudate.<br />The next step was investigation of stability of produced co-extrudate. For this purpose, the samples were stored in a climate chamber capable of setting temperature, relative humidity and air circulation. Modified Schaal-oven test was used to monitor the stability of the product. Modification of the method consisted in adjusting the relative humidity at a constant value of 40 %, which is not required by a classical method. Such a high humidity was selected based on the relative humidity at a constant value of 40 %, which is not required by a classical method. Such a high humidity was selected based on the relative humidity of air, which was measured in the experimental room at the moment. Commercial carvacrol (200 mg/100g of co-extrudate), vitamin E (135 mg/100 g of co-extrudate) and a mixture of these<br />two antioxidants were added to the samples in order to investigate the influence of antioxidants on the oxidative stability of the product. Peroxide value (PV), FFA and fatty acid composition were determined in order to monitor oxidative and chemical changes in co-extrudate. Microbial changes were also examined in the functional feed compound. The most powerful antioxidant effect in this experiment had vitamin E, and a mixture of vitamin E and carvacrol did not show a synergistic effect. The fatty acid compostion during storage was not significantly changed in any sample. On the other hand, extrusion process showed a statistically significant effect (p = 0.032) on the reduction of total number of microorganisms in feed, and the lowest value of the total number of microorganisms (600 cfu/g) was observed in the sample with added<br />carvacrol.</p>

<p>Cilj istraživanja u okviru ove teze je bio da se ispita mogućnost upotrebe pogače uljane tikve golice, nusproizvoda pri proizvodnji devičanskog ulja, za proizvodnju namaza sličnom kikiriki maslacu, kako po spolja&scaron;njem izgledu i teksturi, tako i po reolo&scaron;koj stabilnosti. Namazi su formulisani tako da imaju visok sadržaj omega-6 i omega-3 masnih kiselina, uz njihov izbalansirani odnos prema principima kvalitetne ishrane i preporukama nutricionista, prijatna senzorska svojstva i dobru oksidativnu stabilnost. Upotrebom dvo-faktorskog eksperimentalnog dizajna na pet nivoa i metode odzivnih povr&scaron;ina, kao i statističke analize podataka, izvr&scaron;ena je optimizacija tehnolo&scaron;kog procesa za proizvodnju namaza sa definisanim poželjnim funkcionalnim karakteristikama proizvoda sa nutricionističkog i teksturalnog aspekta. Rezultati su pokazali da je pogača (na 100 g proizvoda) veoma bogata mineralima, uz izuzetno visok sadržaj fosfora, gvožđa, magnezijuma i cinka koji prevazilazi 100% dnevnih potreba prema Pravilniku (2004), a takođe sadrži i velike količine mangana, kalijuma i bakra, te opravdava valorizaciju iste za proizvodnju nutritivno visokovrednog namaza. Devičansko tikvino ulje, poreklom iz pogače, je znatno doprinelo i nutritivnoj vrednosti namaza, budući da je isto bogato omega-6 masnim kiselinama (51.04%) i &gamma;-tokoferolima (704 mg/kg). Konopljino ulje je veoma uticalo na senzornu ocenu namaza, pre svega na ukus i teksturu, kao i na oksidativnu stabilnost. Ustanovljeno je da rok trajanja namaza zavisi od stepena oksidacije ulja u njegovom sastavu, pre svega od količine i kvaliteta konopljinog ulja, i može biti najduže do 6 meseci pri sobnoj temperaturi čuvanja. Utvrđeno je da izdvajanje ulja na povr&scaron;ini namaza zavisi od količine dodatog stabilizatora, a najbolji rezultati su postignuti dodatkom 1.6% stabilizatora. Optimalna vrednost za dobijanje namaza najprihvatljivijeg nutritivnog i senzornog kvaliteta, oksidativne stabilnosti i teksture, je sadržaj stabilizatora od 1.2-1.4% uz 40-60% dodatog konopljinog ulja u masnu fazu proizvoda. Svi proizvedeni namazi su sadržali esencijalnu omega-3 masnu kiselinu uz mogu&scaron;nost deklarisanja kao &bdquo;izvor omega-3 polinezasićenih masnih kiselina&ldquo;, od kojih su pojedini uzorci imali vrlo visok sadržaj (0.98 i 1.24 g) po konzumnoj jednici (15 g). Svi proizvedeni namazi su sadržali i omega-6 masne kiseline, od kojih su pojedini uzorci imali visok sadržaj po konzumnoj jedinici (2.5-3 g), uz mogućnost deklarisanja kao &bdquo;izvor omega-6 polinezasićenih masnih kiselina&ldquo;. Svi namazi (izuzev jednog) su imali odlično izbalansiran odnos između omega-6 i omega-3 masnih kiselina (2-3:1).</p> / <p> The goal of this research was to investigate the possible use of hull-less pumpkin seed oil press cake, a by-product of the pumpkin seed oil pressing process, for the manufacturing of a spread. The spread would be similar to a peanut butter, in appearance, texture and rheological stability. Spreads were formulated in such way that they would have pleasant sensory attributes, good oxidative stability with a high omega-6 and omega-3 fatty acids content, while providing their balanced ratio based on modern healthy food principles as recommended by nutritionists. Optimization of the spread manufacturing technology was conducted based on the results of the two factorial experimental design on five levels using response surface methodology and statistical analysis (ANOVA). Desirable functional characteristics of the spreads were defined based on nutritional and textural attributes. Results have shown that pumpkin seed oil press cake (per 100 g) is very rich in minerals, especially phosphorus iron, magnesium and zinc that exceeds recommended daily intake (Pravilnik, 2004) over 100%. In addition, it contains high amounts of manganese, potassium and copper, which justifies the use of the seed oil press cake for investigation of the possibility for its use in nutritious spread manufacturing. Cold pressed hull-less pumpkin oil significantly contributed to the nutritional value of the spreads, since it is rich in omega-6 fatty acids (51.04%) and &gamma;-tocopherols (704 mg/kg). Hemp oil had a significant effect on the sensory evaluation of the spreads, primarily on the taste and texture, as well as the oxidative stability of the spreads. It was confirmed that the shelf life of the spreads depended on the oxidation of the oils present in the spread, and primarily depended on the hemp oil quantity and quality. All spreads had a shelf life of maximum 6 months at ambient temperature. It was also confirmed that oil separation on the spreads&rsquo; surface depended on the amount of added stabilizer, where the best results were achieved with the addition of 1.6% stabilizer. Considering nutritional value, sensory evaluation, oxidative stability and texture, the optimal spreads were made using the stabilizer at 1.2-1.4% and hemp oil at 40-60% added to the fatty phaze of the spread. All prepared spreads contained omega-3 essential fatty acid that could be declared as a &ldquo;source of omega-3 polyunsaturated fatty acids&ldquo;. Few samples had a very high content of omega-3 fatty acids (0.98 and 1.24 g) per serving size 15 g). In addition, all prepared spreads contained omega-6 fatty acids, where some samples had a high content of omega-6 fatty acids per serving size (2.5-3 g), and could be declared as a &ldquo;source of omega-6 polyunsaturated fatty acids&ldquo;. All prepared spreads (except one) had a well balanced ratio between omega-6 and omega-3 fatty acids (2-3:1).</p>

Dans les syndromes coronariens aigus, le ticagrelor améliore la survie comparativement au clopidogrel. Les effets pléiotropiques de ce médicament ne sont pas entièrement compris. La métabolomique non ciblée, couplée avec des analyses computationnelles, a le potentiel d’élucider les changements pathophysiologiques du métabolisme cellulaire associés aux différentes maladies et aux traitements. L’objectif de cette étude est de dévoiler une signature métabolomique discriminante entre le clopidogrel et le ticagrelor dans le traitement de l’infarctus du myocarde avec élévation du segment ST (STEMI). La population de l’étude est formée de 175 participants de l’essai PLATO avec STEMI ayant subi une intervention percutanée (PCI), randomisés à recevoir le clopidogrel (n=88) ou le ticagrelor (n=87), appariés pour l’âge, le sexe, le statut de dyslipidémie et de diabète. Un profil métabolomique plasmatique non ciblé, obtenu par spectrométrie de masse (MS), est effectué pour chaque individu à l’état de base (BL; maladie aiguë) et au congé de l’hôpital après en moyenne 4 jours d’hospitalisation (DC; état post-traitement). L’étude des données a été effectuée par une analyse de quantification différentielle, une analyse de la variance, la construction d'un réseau de co-modulation et des techniques d'apprentissage automatique. Huit (8) métabolites étaient modulés de façon différentielle entre les deux groupes de traitement au congé, dont six (6) appartenant aux voies de biosynthèse des acides gras polyinsaturés omega-3 (n3) et omega-6 (n6). Les participants traités avec ticagrelor présentent des niveaux plasmatiques significativement plus élevés des acides gras suivants : α et de γ-linolénate (n3 and n6), dihomo-linolénate (n6), stéaridonate (n3), docosahexaenoate (DHA; n3), eicosapentaenoate (EPA; n3) et arachidonate (AA; n6). Chez les patients avec STEMI traités par PCI, des analyses de métabolomique non ciblées révèlent que les métabolites impliqués dans la biosynthèse des omega-3 et des omega-6 sont significativement plus élevé au congé dans le groupe traité par le ticagrelor, comparativement au clopidogrel, suggérant que le remodelage du réseau métabolique après un infarctus du myocarde pourrait interagir avec la réponse aux antiplaquettaires. / Background: In acute coronary syndromes, ticagrelor improved survival compared to clopidogrel. Pleiotropic effects of this drug are not entirely elucidated. Untargeted metabolomics coupled with computational analyses has the potential to help understanding pathophysiological changes of cellular metabolism associated with different disease states and therapies. Objectives: The purpose of this study is to unveil a discriminant metabolomics signature comparing ST-elevation myocardial infarction (STEMI) patients treated with clopidogrel and ticagrelor. Methods: The study population consists of 175 participants with STEMI from the PLATO Trial who underwent percutaneous coronary intervention (PCI), randomized to receive clopidogrel (n=88) or ticagrelor (n=87), matched for age, sex, dyslipidemia and diabetes status. Untargeted mass spectrometry (MS)-based metabolomics profiling in plasma was performed at baseline (BL; acute disease state) and repeated at hospital discharge after an average of 4 days of hospitalization (DC; post-treatment state), for each individual. Data analysis was done through differential quantification analysis, analysis of variance, co-modulation network construction and machine learning techniques. Results: Eight (8) metabolites were differentially modulated by treatment between groups at DC, six (6) of which belong to the polyunsaturated fatty acids omega-3 (n3) and omega-6 (n6) biosynthesis pathways. Participants treated with ticagrelor harbor a significantly higher plasmatic level of α and γ linolenate (n3 and n6), dihomo-linolenate (n6), stearidonate (n3), docosahexaenoate (DHA; n3), eicosapentaenoate (EPA; n3) and arachidonate (AA; n6). Conclusion: In patients with STEMI undergoing PCI, untargeted metabolomics reveals that metabolites involved in omega-3 and omega-6 biosynthesis are significantly higher at discharge in the ticagrelor treatment group when compared to clopidogrel, suggesting that the remodeling of the metabolic network after myocardial infarction may interact with the response to antiplatelet drugs.