Yes / We investigated red blood cell (RBC) PUFA profiles, and the predictive value of RBC EPA content for tumour EPA exposure and clinical outcomes, in the EMT study, a randomised trial of EPA in patients awaiting colorectal cancer (CRC) liver metastasis surgery (A.J. Cockbain et al., 2014). There was a significant increase in RBC EPA in the EPA group (n=43; median intervention 30 days; mean absolute 1.26 [±0.14]% increase; P<0.001), but not in the placebo arm (n=45). EPA incorporation varied widely in EPA users and was not explained by treatment duration or compliance. There was little evidence of ‘contamination’ in the placebo group. The EPA level predicted tumour EPA content (r=0.36; P=0.03). Participants with post-treatment EPA ≥1.22% (n=49) had improved OS compared with EPA <1.22% (n=29; HR 0.42[95%CI 0.16–0.95]). RBC EPA content should be evaluated as a biomarker of tumour exposure and clinical outcomes in future EPA trials in CRC patients.

Introdução: O PYY é um peptídeo regulador da saciedade produzido pelas células intestinais em resposta à chegada intraluminal de nutrientes. Objetivos: O presente estudo objetivou avaliar o efeito de sobrecargas agudas de gorduras saturadas (SAT) e monoinsaturadas (MUFA) na secreção aguda de PYY em ratos Wistar normais e após insulinorresistência induzida por dieta hiperlipídica. Métodos: Em experimento controlado, ratos Wistar foram submetidos a uma dieta altamente gordurosa (HFD) (55% de gordura) por 19 semanas (n=15) ou à dieta normal (GC) pelo mesmo tempo (ração ad libitum) (n=15). Ao final de 14 semanas foi realizado um experimento cross-over onde foi avaliada a resposta secretória de PYY sérico nos tempos basal e 60 minutos após sobrecarga oral lipídica isovolumétrica, por meio de gavagem, ajustadas para o peso, administrada de forma aleatória, em dias diferentes, constituídas por ácidos graxos saturados (SAT-banha de porco) ou monoinsaturados (MUFA-óleo de oliva) ou água (CONT). Diferenças entre médias e grupos foram avaliadas por meio de ANOVA de medidas repetidas e associação por regressão linear simples. Resultados: Em relação ao PYY, no grupo com dieta normal, ambas sobrecargas MUFA e SAT elevaram a resposta secretória de PYY significativamente em relação aos seus respectivos basais: MUFA-Basal 2,18 (± 0,24) vs. MUFA-60min 2,30 (± 0,26) pg/ml e SAT-basal 2,21 (± 0.25) pg/ml vs. SAT- 60min 2,29 (± 0,22) pg/ml ANOVA múltiplas entradas p= 0,019 intragrupos; entretanto, sem diferença entre grupos MUFA e SAT (ANOVA múltiplas entradas entre-grupos p= 0,314). No grupo HFD por outro lado, a sobrecarga SAT reduziu o PYY: SAT-basal 2,16 (± 0.21) pg/ml vs. SAT-60min 2,11 (± 0,30) pg/ml (p= 0,01,intragrupos) enquanto a sobrecarga MUFA manteve o mesmo aumento MUFAbasal 2,15pg/ml vs. MUFA-60min 2,22 (± 0.22) pg/ml. p=0,019 (intragrupos). A administração de água (CONT) também reduziu o PYY em relação ao basal, tanto com na dieta normal (p= 0,0091) como na dieta (HFD) (p= 0,0091), mas sem diferença entre os grupos (p= 0,7433). Conclusão: Em ratos Wistar, as sobrecargas lipídicas, tanto de MUFA como de gordura saturadas, aumentam agudamente a secreção de PYY. Entretanto, em ratos Wistar tornados insulinorresistentes através de uma dieta altamente rica em gordura saturada, a mesma sobrecarga de gordura saturada perde a capacidade de estimular os níveis de PYY, enquanto à resposta ao MUFA segue preservada. Esta resposta paradoxal a gorduras saturadas poderia representar um dano celular causado pela insulinorresistência ao tecido intestinal interferindo no aparato secretor de PYY em resposta a este nutriente. Estudos no tecido intestinal precisam ser realizados para identificar possíveis fatores envolvidos e suas implicações no controle da saciedade pelo PYY em indivíduos insulinorresistentes. / Background: PYY is a gut peptide released by L-cells from the intestine after a meal. Objective: The present study aimed to evaluate the effect of acute overloads of saturated fatty acids (SAT) and monounsaturated fatty acids (MUFA) on PYY release in normal and diet induced insulin resistant wistar rats. Methods: a nineteen weeks experiment was conducted with 30 wistar rats that were allocated into two groups: high fat diet (HFD group) (n=15) with diet composition of 55% of lard and 45% standard chow and control group (CG) (n=15). Both groups received water and food ad libitum. Later a cross-over experiment was conducted to evaluate PYY secretory response 60 minutes after two different lipid overloads (SAT-lard; MUFAolive oil) and water (CONT), adjusted by weight, all isovolumetric and lipids were isocaloric, randomly administered in different days. Mean differences were analyzed by repeated measures ANOVA and association by simple linear regression. Results: Both MUFA and SAT overloads significantly increased PYY release in the CG in comparison with baselines: MUFA-Baseline 2,18±0,24 vs. MUFA-60min 2,30±0,26pg/ml and SAT-baseline 2,21±0.25pg/ml vs. SAT-60min 2,29±0,22 pg/ml ANOVA multiple entry p=0,019 intra-group, however without difference between MUFA and SAT (ANOVA multiple entry inter-group p=0,314). In the other hand, HFD SAT overload significantly decreased PYY release: SAT-baseline 2,16±0.21 pg/ml vs. SAT-60min 2,11±0,30 pg/ml (p=0,01,intra-group) while MUFA overload was able to keep the increase on PYY release MUFA-baseline 2,15pg/ml vs. MUFA-60min 2,22±0.22 pg/ml. p=0,019 (intra-group). Water overload (CONT) also reduced PYY release in comparison with baseline in both CG (p=0,0091) and HFD (p=0,0091), without difference between them (p= 0,7433). Conclusion: MUFA and SAT overloads increase PYY release after 60 minutes in normal wistar rats. However, when became high fat diet induced insulin resistant the SAT overload looses the capacity to stimulate PYY release, while MUFA response keeps preserved. This paradoxal finding to saturated fatty acids could indicate a cellular damage caused by insulin resistance in the intestinal tissue which compromises PYY secretory apparatus in response to this nutrient. Studies in the intestinal tissue must be conducted in order to identify possible factors involved and its implications in satiety signals PYY mediated in insulin resistance individuals.

<p>This thesis describes the structural studies of four different proteins from two organisms. Xyloglucan endotransglycosylases, XETs, are involved in plant cell wall expansion and remodeling by splitting and reconnecting xyloglucan-cellulose crosslinks. The first crystal structure of a XET enzyme has been determined to 1.8 Å. The structure provides insights into how XETs are able to bind a heavily branched xyloglucan sugar, as well as hints about the XET-transglycosylation mechanism.</p><p><i>Mycobacterium tuberculosis</i> (Mtb) is the cause of enormous human mortality each year. Despite the sequencing of the complete Mtb-genome, the biological function of a large fraction of the <i>M. tuberculosis </i>proteins is still unknown. We here report the crystal structures of three such proteins, Rv2740, Rv0216 and Rv0130. Rv2740 forms a Cystatin α+b fold with a deep active site pocket similar to a limonene-1,2-epoxide hydrolase from <i>Rhodococcus erythropolis</i>. However, in contrast to the small limonene-based substrate of the <i>Rhodococcus</i> enzyme, Rv2740 is able to degrade large fatty acid and sterol epoxides, giving suggestions for the physiological substrates of this enzyme.</p><p>The structure of <i>M. tuberculosis</i> Rv0216 exhibits a so-called double hotdog fold. Rv0216 shows similarity to a number of enzymes using thiol esters as substrates, including several <i>R</i>-enoyl hydratases and β-hydroxyacyl dehydratases. However, only parts of the hydratase / dehydratase catalytic site are conserved in Rv0216. Rv0130 in contrast, contains a highly conserved <i>R</i>-hydratase motif, housed in a dimer of two single hotdog folded molecules. This active site is situated in a long tunnel, formed by a sharp kink in the Rv0130 central helix. A number of previously predicted single / double hotdog folded proteins from <i>M. tuberculosis</i> seem to feature a similar substrate-binding tunnel, indicating that Rv0130 as well as some of these proteins, might act on long fatty enoyl chains. </p>

This thesis describes the structural studies of four different proteins from two organisms. Xyloglucan endotransglycosylases, XETs, are involved in plant cell wall expansion and remodeling by splitting and reconnecting xyloglucan-cellulose crosslinks. The first crystal structure of a XET enzyme has been determined to 1.8 Å. The structure provides insights into how XETs are able to bind a heavily branched xyloglucan sugar, as well as hints about the XET-transglycosylation mechanism. Mycobacterium tuberculosis (Mtb) is the cause of enormous human mortality each year. Despite the sequencing of the complete Mtb-genome, the biological function of a large fraction of the M. tuberculosis proteins is still unknown. We here report the crystal structures of three such proteins, Rv2740, Rv0216 and Rv0130. Rv2740 forms a Cystatin α+b fold with a deep active site pocket similar to a limonene-1,2-epoxide hydrolase from Rhodococcus erythropolis. However, in contrast to the small limonene-based substrate of the Rhodococcus enzyme, Rv2740 is able to degrade large fatty acid and sterol epoxides, giving suggestions for the physiological substrates of this enzyme. The structure of M. tuberculosis Rv0216 exhibits a so-called double hotdog fold. Rv0216 shows similarity to a number of enzymes using thiol esters as substrates, including several R-enoyl hydratases and β-hydroxyacyl dehydratases. However, only parts of the hydratase / dehydratase catalytic site are conserved in Rv0216. Rv0130 in contrast, contains a highly conserved R-hydratase motif, housed in a dimer of two single hotdog folded molecules. This active site is situated in a long tunnel, formed by a sharp kink in the Rv0130 central helix. A number of previously predicted single / double hotdog folded proteins from M. tuberculosis seem to feature a similar substrate-binding tunnel, indicating that Rv0130 as well as some of these proteins, might act on long fatty enoyl chains.

No description available.

The objectives were to 1) conduct a meta-analysis to assess the association between alpha-linolenic acid (ALA) and prostate cancer; 2) analyze a trial of ALA on coronary heart disease with PSA as a post hoc outcome; 3) assess the effect of trial serum and also ALA directly on LNCaP cell growth. 1) The ALA meta-analysis of prospective and case-control studies showed no overall effect on prostate cancer. However, removal of one study from the analysis of prospective studies changed the result to a significant protective effect (RR=0.91; 95%CI:0.83,0.99). 2) No significant treatment difference was seen in the change in PSA in the randomized controlled trial. 3) The ALA treatment serum from the clinical trial did not affect LNCaP cell growth. However, ALA decreased LNCaP cell growth in a dose dependent manner when added to cell culture. The results provide no positive evidence for an effect of ALA on prostate cancer.

The objectives were to 1) conduct a meta-analysis to assess the association between alpha-linolenic acid (ALA) and prostate cancer; 2) analyze a trial of ALA on coronary heart disease with PSA as a post hoc outcome; 3) assess the effect of trial serum and also ALA directly on LNCaP cell growth. 1) The ALA meta-analysis of prospective and case-control studies showed no overall effect on prostate cancer. However, removal of one study from the analysis of prospective studies changed the result to a significant protective effect (RR=0.91; 95%CI:0.83,0.99). 2) No significant treatment difference was seen in the change in PSA in the randomized controlled trial. 3) The ALA treatment serum from the clinical trial did not affect LNCaP cell growth. However, ALA decreased LNCaP cell growth in a dose dependent manner when added to cell culture. The results provide no positive evidence for an effect of ALA on prostate cancer.

Introdução: O PYY é um peptídeo regulador da saciedade produzido pelas células intestinais em resposta à chegada intraluminal de nutrientes. Objetivos: O presente estudo objetivou avaliar o efeito de sobrecargas agudas de gorduras saturadas (SAT) e monoinsaturadas (MUFA) na secreção aguda de PYY em ratos Wistar normais e após insulinorresistência induzida por dieta hiperlipídica. Métodos: Em experimento controlado, ratos Wistar foram submetidos a uma dieta altamente gordurosa (HFD) (55% de gordura) por 19 semanas (n=15) ou à dieta normal (GC) pelo mesmo tempo (ração ad libitum) (n=15). Ao final de 14 semanas foi realizado um experimento cross-over onde foi avaliada a resposta secretória de PYY sérico nos tempos basal e 60 minutos após sobrecarga oral lipídica isovolumétrica, por meio de gavagem, ajustadas para o peso, administrada de forma aleatória, em dias diferentes, constituídas por ácidos graxos saturados (SAT-banha de porco) ou monoinsaturados (MUFA-óleo de oliva) ou água (CONT). Diferenças entre médias e grupos foram avaliadas por meio de ANOVA de medidas repetidas e associação por regressão linear simples. Resultados: Em relação ao PYY, no grupo com dieta normal, ambas sobrecargas MUFA e SAT elevaram a resposta secretória de PYY significativamente em relação aos seus respectivos basais: MUFA-Basal 2,18 (± 0,24) vs. MUFA-60min 2,30 (± 0,26) pg/ml e SAT-basal 2,21 (± 0.25) pg/ml vs. SAT- 60min 2,29 (± 0,22) pg/ml ANOVA múltiplas entradas p= 0,019 intragrupos; entretanto, sem diferença entre grupos MUFA e SAT (ANOVA múltiplas entradas entre-grupos p= 0,314). No grupo HFD por outro lado, a sobrecarga SAT reduziu o PYY: SAT-basal 2,16 (± 0.21) pg/ml vs. SAT-60min 2,11 (± 0,30) pg/ml (p= 0,01,intragrupos) enquanto a sobrecarga MUFA manteve o mesmo aumento MUFAbasal 2,15pg/ml vs. MUFA-60min 2,22 (± 0.22) pg/ml. p=0,019 (intragrupos). A administração de água (CONT) também reduziu o PYY em relação ao basal, tanto com na dieta normal (p= 0,0091) como na dieta (HFD) (p= 0,0091), mas sem diferença entre os grupos (p= 0,7433). Conclusão: Em ratos Wistar, as sobrecargas lipídicas, tanto de MUFA como de gordura saturadas, aumentam agudamente a secreção de PYY. Entretanto, em ratos Wistar tornados insulinorresistentes através de uma dieta altamente rica em gordura saturada, a mesma sobrecarga de gordura saturada perde a capacidade de estimular os níveis de PYY, enquanto à resposta ao MUFA segue preservada. Esta resposta paradoxal a gorduras saturadas poderia representar um dano celular causado pela insulinorresistência ao tecido intestinal interferindo no aparato secretor de PYY em resposta a este nutriente. Estudos no tecido intestinal precisam ser realizados para identificar possíveis fatores envolvidos e suas implicações no controle da saciedade pelo PYY em indivíduos insulinorresistentes. / Background: PYY is a gut peptide released by L-cells from the intestine after a meal. Objective: The present study aimed to evaluate the effect of acute overloads of saturated fatty acids (SAT) and monounsaturated fatty acids (MUFA) on PYY release in normal and diet induced insulin resistant wistar rats. Methods: a nineteen weeks experiment was conducted with 30 wistar rats that were allocated into two groups: high fat diet (HFD group) (n=15) with diet composition of 55% of lard and 45% standard chow and control group (CG) (n=15). Both groups received water and food ad libitum. Later a cross-over experiment was conducted to evaluate PYY secretory response 60 minutes after two different lipid overloads (SAT-lard; MUFAolive oil) and water (CONT), adjusted by weight, all isovolumetric and lipids were isocaloric, randomly administered in different days. Mean differences were analyzed by repeated measures ANOVA and association by simple linear regression. Results: Both MUFA and SAT overloads significantly increased PYY release in the CG in comparison with baselines: MUFA-Baseline 2,18±0,24 vs. MUFA-60min 2,30±0,26pg/ml and SAT-baseline 2,21±0.25pg/ml vs. SAT-60min 2,29±0,22 pg/ml ANOVA multiple entry p=0,019 intra-group, however without difference between MUFA and SAT (ANOVA multiple entry inter-group p=0,314). In the other hand, HFD SAT overload significantly decreased PYY release: SAT-baseline 2,16±0.21 pg/ml vs. SAT-60min 2,11±0,30 pg/ml (p=0,01,intra-group) while MUFA overload was able to keep the increase on PYY release MUFA-baseline 2,15pg/ml vs. MUFA-60min 2,22±0.22 pg/ml. p=0,019 (intra-group). Water overload (CONT) also reduced PYY release in comparison with baseline in both CG (p=0,0091) and HFD (p=0,0091), without difference between them (p= 0,7433). Conclusion: MUFA and SAT overloads increase PYY release after 60 minutes in normal wistar rats. However, when became high fat diet induced insulin resistant the SAT overload looses the capacity to stimulate PYY release, while MUFA response keeps preserved. This paradoxal finding to saturated fatty acids could indicate a cellular damage caused by insulin resistance in the intestinal tissue which compromises PYY secretory apparatus in response to this nutrient. Studies in the intestinal tissue must be conducted in order to identify possible factors involved and its implications in satiety signals PYY mediated in insulin resistance individuals.

Introdução: O PYY é um peptídeo regulador da saciedade produzido pelas células intestinais em resposta à chegada intraluminal de nutrientes. Objetivos: O presente estudo objetivou avaliar o efeito de sobrecargas agudas de gorduras saturadas (SAT) e monoinsaturadas (MUFA) na secreção aguda de PYY em ratos Wistar normais e após insulinorresistência induzida por dieta hiperlipídica. Métodos: Em experimento controlado, ratos Wistar foram submetidos a uma dieta altamente gordurosa (HFD) (55% de gordura) por 19 semanas (n=15) ou à dieta normal (GC) pelo mesmo tempo (ração ad libitum) (n=15). Ao final de 14 semanas foi realizado um experimento cross-over onde foi avaliada a resposta secretória de PYY sérico nos tempos basal e 60 minutos após sobrecarga oral lipídica isovolumétrica, por meio de gavagem, ajustadas para o peso, administrada de forma aleatória, em dias diferentes, constituídas por ácidos graxos saturados (SAT-banha de porco) ou monoinsaturados (MUFA-óleo de oliva) ou água (CONT). Diferenças entre médias e grupos foram avaliadas por meio de ANOVA de medidas repetidas e associação por regressão linear simples. Resultados: Em relação ao PYY, no grupo com dieta normal, ambas sobrecargas MUFA e SAT elevaram a resposta secretória de PYY significativamente em relação aos seus respectivos basais: MUFA-Basal 2,18 (± 0,24) vs. MUFA-60min 2,30 (± 0,26) pg/ml e SAT-basal 2,21 (± 0.25) pg/ml vs. SAT- 60min 2,29 (± 0,22) pg/ml ANOVA múltiplas entradas p= 0,019 intragrupos; entretanto, sem diferença entre grupos MUFA e SAT (ANOVA múltiplas entradas entre-grupos p= 0,314). No grupo HFD por outro lado, a sobrecarga SAT reduziu o PYY: SAT-basal 2,16 (± 0.21) pg/ml vs. SAT-60min 2,11 (± 0,30) pg/ml (p= 0,01,intragrupos) enquanto a sobrecarga MUFA manteve o mesmo aumento MUFAbasal 2,15pg/ml vs. MUFA-60min 2,22 (± 0.22) pg/ml. p=0,019 (intragrupos). A administração de água (CONT) também reduziu o PYY em relação ao basal, tanto com na dieta normal (p= 0,0091) como na dieta (HFD) (p= 0,0091), mas sem diferença entre os grupos (p= 0,7433). Conclusão: Em ratos Wistar, as sobrecargas lipídicas, tanto de MUFA como de gordura saturadas, aumentam agudamente a secreção de PYY. Entretanto, em ratos Wistar tornados insulinorresistentes através de uma dieta altamente rica em gordura saturada, a mesma sobrecarga de gordura saturada perde a capacidade de estimular os níveis de PYY, enquanto à resposta ao MUFA segue preservada. Esta resposta paradoxal a gorduras saturadas poderia representar um dano celular causado pela insulinorresistência ao tecido intestinal interferindo no aparato secretor de PYY em resposta a este nutriente. Estudos no tecido intestinal precisam ser realizados para identificar possíveis fatores envolvidos e suas implicações no controle da saciedade pelo PYY em indivíduos insulinorresistentes. / Background: PYY is a gut peptide released by L-cells from the intestine after a meal. Objective: The present study aimed to evaluate the effect of acute overloads of saturated fatty acids (SAT) and monounsaturated fatty acids (MUFA) on PYY release in normal and diet induced insulin resistant wistar rats. Methods: a nineteen weeks experiment was conducted with 30 wistar rats that were allocated into two groups: high fat diet (HFD group) (n=15) with diet composition of 55% of lard and 45% standard chow and control group (CG) (n=15). Both groups received water and food ad libitum. Later a cross-over experiment was conducted to evaluate PYY secretory response 60 minutes after two different lipid overloads (SAT-lard; MUFAolive oil) and water (CONT), adjusted by weight, all isovolumetric and lipids were isocaloric, randomly administered in different days. Mean differences were analyzed by repeated measures ANOVA and association by simple linear regression. Results: Both MUFA and SAT overloads significantly increased PYY release in the CG in comparison with baselines: MUFA-Baseline 2,18±0,24 vs. MUFA-60min 2,30±0,26pg/ml and SAT-baseline 2,21±0.25pg/ml vs. SAT-60min 2,29±0,22 pg/ml ANOVA multiple entry p=0,019 intra-group, however without difference between MUFA and SAT (ANOVA multiple entry inter-group p=0,314). In the other hand, HFD SAT overload significantly decreased PYY release: SAT-baseline 2,16±0.21 pg/ml vs. SAT-60min 2,11±0,30 pg/ml (p=0,01,intra-group) while MUFA overload was able to keep the increase on PYY release MUFA-baseline 2,15pg/ml vs. MUFA-60min 2,22±0.22 pg/ml. p=0,019 (intra-group). Water overload (CONT) also reduced PYY release in comparison with baseline in both CG (p=0,0091) and HFD (p=0,0091), without difference between them (p= 0,7433). Conclusion: MUFA and SAT overloads increase PYY release after 60 minutes in normal wistar rats. However, when became high fat diet induced insulin resistant the SAT overload looses the capacity to stimulate PYY release, while MUFA response keeps preserved. This paradoxal finding to saturated fatty acids could indicate a cellular damage caused by insulin resistance in the intestinal tissue which compromises PYY secretory apparatus in response to this nutrient. Studies in the intestinal tissue must be conducted in order to identify possible factors involved and its implications in satiety signals PYY mediated in insulin resistance individuals.

Adipositas und die damit verbundenen Folgeerkrankungen sind eine der zentralen Gesund-heitsherausforderungen unserer Zeit. Dauerhafte Adipositas führt zu einer Dysregulation fettgewebseigener Peptidhormone. Diese sogenannten Adipokine stellen ein Verbindungsglied zwischen Fettgewebsakkumulation und den vielfältigen Adipositaskomplikationen des gesamten Organismus dar. Adipocyte fatty acid binding protein (AFABP) wurde in den letzten Jahren als zirkulierendes Adipokin mit diabetogenen, proinflammatorischen und proateriosklerotischen Effekten etabliert. Zu Beginn der Dissertation lagen unzureichende Erkenntnisse über die Elimination von AFABP sowie die Regulation des Adipokins bei eingeschränkter Nierenfunktion vor. Aus diesem Grund untersucht die vorliegende Arbeit die AFABP-Regulation in Abhängigkeit von der Nierenfunktion in 532 Patienten mit chronischer Niereninsuffizienz (Studienpopulation 1) und 32 Patienten mit akuter Nierenfunktionsverminderung nach Nephrektomie (Studienpopulation 2). In beiden Kohorten stiegen die medianen AFABP-Serumkonzentrationen mit abfallender Nierenfunktion an. Zudem waren Marker der Nierenfunktion in beiden Studienpopulationen die stärksten unabhängigen Prädiktoren für zirkulierendes AFABP. Untersuchungen aus der Arbeitsgruppe zur AFABP-Regulation in einem Rattenmodell der akuten Niereninsuffizienz unterstützen die klinischen Studienergebnisse. Zusammenfassend zeigen diese Ergebnisse zum ersten Mal signifikant steigende AFABP-Serumspiegel bei chronischer und akuter Nierenfunktionsstörung, sowie bei akutem Abfall der Nierenfunktion. Diese Befunde stützen die Hypothese, dass AFABP renal eliminiert wird. Inwiefern AFABP darüber hinaus in die Pathogenese der chronischen Niereninsuffizienz eingreift, muss in weiterführenden Studien beleuchtet werden.