Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / This work aimed to develop refining processes, chemical alcoholysis followed by separation of fatty acids using the complexation with urea technique for the synthesis of poly-unsaturated esters from waste of fish oils. The special crude fish oil was purchased from Company Campestre - SÃo Paulo. Initially this oil has undergone a process of physical and chemical refining. From the refined oil, an alcoholysis process was carried out to obtain the mixture of free fatty acids. From the hydrolyzed material were obtained 32.78% p/p of PUFAs against 19.73% p/p of ω-3 concentrates. The free fatty acids were separated using the complexation with urea technique. The best operating conditions for separation of the fatty acids was: ratio 7:1 (urea / oil) and the crystallization temperature at -23ÂC for a time of 20 hours. After treatment of the material, the total PUFAs production was 47.87%, a ω-3 concentration of 27.59% with a saturated fraction of 4.48%. When the temperature was raised to -10ÂC, the PUFAs production was halved, reaching the value of 28.08% and 25.49% of ω-3 which was slightly altered and a saturated fraction of 42.44%. For the ester synthesis was mounted a statistical factor of two levels in order to determine the parameters which optimized the process. In the synthesis phase, the combination of temperature, glycerin concentration and catalyst was significant, and it was observed a greater influence of the glycerin concentration due to the excessive use of glycerin to favor the formation of the ester. After the analysis of the kinetic results was observed that the interactions temperature-glycerin and temperature-glycerin-catalyst were not significant (below 95%). The response interaction graphic showed the least free fatty acids index after one hour of reaction, and that the greater interaction was glycerin (5%)-catalyst (3%). It was concluded that the yields to obtain the polyunsaturated ω-3 and ω -6 from the waste of fish oil were satisfactory (85,3%). Therefore, it is concluded that it is feasible the synthesis of polyunsaturated esters of marine oils from fish waste, because this technology provides important results to avoid environmental impacts, reduce imports of fish oils and, consequently, reduce improper fishing. The aquaculture industry may be stocked with diets enriched with EPA and DHA for shrimp and fish farming, besides contributing to supply ω-3 for nutraceutical purposes. / Este trabalho teve o objetivo de desenvolver os processos de refino, alcoÃlise quÃmica seguida da separaÃÃo dos Ãcidos graxos utilizando a tÃcnica da complexaÃÃo com urÃia para a sÃntese de Ãsteres poli-insaturados a partir de resÃduos de Ãleos de pescado. O Ãleo bruto especial de peixe foi adquirido da Empresa Campestre â SÃo Paulo. Inicialmente este Ãleo sofreu um processo de refino fÃsico e quÃmico. A partir do Ãleo refinado, foi realizado um processo de alcoÃlise para se obter a mistura de Ãcidos graxos livres. Do material hidrolisado, foram obtidos 32,78% p/p de PUFAs contra 19,73% p/p de concentrados de ω-3. Os Ãcidos graxos livres foram separados utilizando-se a tÃcnica da complexaÃÃo com urÃia. As melhores condiÃÃes operacionais para separaÃÃo dos Ãcidos graxos foram: a relaÃÃo 7:1 (urÃia/Ãleo) e a temperatura de cristalizaÃÃo a -23ÂC por um tempo de 20 horas. ApÃs o tratamento do material, a produÃÃo total de PUFAs foi de 47,87%, uma concentraÃÃo de ω-3 de 27,59% com uma fraÃÃo saturada de 4,48%. Quando se elevou a temperatura para -10ÂC, a produÃÃo de PUFAs reduziu pela metade, atingindo o valor de 28,08% e 25,49% de ω-3, que pouco foi alterada e uma fraÃÃo de saturados de 42,44%. Para a sÃntese do Ãster de glicerina foi montado um fatorial estatÃstico de dois nÃveis a fim de se determinar os parÃmetros que otimizaram o processo. Na fase de sÃntese, a conjugaÃÃo de temperatura, concentraÃÃo de glicerina e catalisador foram significantes, tendo sido observado uma maior influÃncia da concentraÃÃo de glicerina, em virtude do uso excessivo de glicerina para favorecer a formaÃÃo do Ãster. ApÃs as anÃlises dos resultados cinÃticos, foi observado que as interaÃÃes temperatura-glicerina e temperatura-glicerina-catalisador nÃo foram significantes (abaixo de 95%). O grÃfico da interaÃÃo para resposta mostrou o menor Ãndice de Ãcidos graxos livres apÃs uma hora de reaÃÃo, e que a maior interaÃÃo foi glicerina (5%)-catalisador (3%). Foi concluÃdo que os rendimentos para obtenÃÃo dos poli-insaturados ω-3 e ω -6 dos resÃduos de Ãleo de pescado foram satisfatÃrios (85,3%). Conclui-se, portanto, que à viÃvel a sÃntese de Ãsteres poli-insaturados de Ãleos marinhos a partir de rejeitos de pescados, pois esta tecnologia proporciona resultados importantes para evitar impactos ambientais, diminuir as importaÃÃes de Ãleos de peixe e, consequentemente, reduzir a pesca indevida. O setor aquÃcola poderà ser abastecido com raÃÃes enriquecidas com EPA e DHA para camarÃes e peixes de cultivo, alÃm de contribuir para oferta de ω-3 para fins nutracÃuticos.

Yes / There remains an unmet need for safe and cost-effective adjunctive treatment of advanced colorectal cancer (CRC). The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and has anti-inflammatory as well as antineoplastic properties. A phase 2 randomised trial of preoperative EPA free fatty acid 2 g daily in patients undergoing surgery for CRC liver metastasis showed no difference in the primary endpoint (histological tumour proliferation index) compared with placebo. However, the trial demonstrated possible benefit for the prespecified exploratory endpoint of postoperative disease-free survival. Therefore, we tested the hypothesis that EPA treatment, started before liver resection surgery (and continued postoperatively), improves CRC outcomes in patients with CRC liver metastasis. Methods and analysis: The EPA for Metastasis Trial 2 trial is a randomised, double-blind, placebo-controlled, phase 3 trial of 4 g EPA ethyl ester (icosapent ethyl (IPE; Vascepa)) daily in patients undergoing liver resection surgery for CRC liver metastasis with curative intent. Trial treatment continues for a minimum of 2 years and maximum of 4 years, with 6monthly assessments, including quality of life outcomes, as well as annual clinical record review after the trial intervention. The primary endpoint is CRC progression-free survival. Key secondary endpoints are overall survival, as well as the safety and tolerability of IPE. A minimum 388 participants are estimated to provide 247 CRC progression events during minimum 2-year follow-up, allowing detection of an HR of 0.7 in favour of IPE, with a power of 80% at the 5% (two sided) level of significance, assuming drop-out of 15%. Ethics and dissemination: Ethical and health research authority approval was obtained in January 2018. All data will be collected by 2025. Full trial results will be published in 2026. Secondary analyses of health economic data, biomarker studies and other translational work will be published subsequently. Trial registration number NCT03428477. / The EMT2 trial is funded by Yorkshire Cancer Research (L387) and is sponsored by the University of Leeds. The EMT2 biospecimen collection is funded by the National Institutes of Health (1R01CA243454-01A1) and is sponsored by the University of Leeds ( governance-ethics@ leeds. ac. uk). Both studies have been adopted to the NIHR Clinical Research Network (CRN) Portfolio (CPMS ID 34700 and 47372, respectively) and have benefited from CRN research staff support.

Human skin has distinct lipid metabolism and production of bioactive lipid mediators that can be modulated by nutritional supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFA), of which eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids exert anti-inflammatory effects. The aims of this project were to gain better understanding of their individual mechanisms in human epidermis and dermis. HaCaT keratinocytes, 46BR.1N fibroblasts, primary human epidermal keratinocytes and dermal fibroblasts were treated with EPA or DHA for 72h and then sham-irradiated or exposed to 15 mJ/cm2 ultraviolet radiation (UVR). Viability was measured by the MTT assay. The expression of cyclooxygenase-2 (COX-2), microsomal prostaglandin synthase-1 (mPGES-1) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) proteins was explored by western blotting. Human skin explants (n=4 donors) were cultured for 3 or 6 days and supplemented with EPA, DHA or vehicle. Culture media were collected to evaluate tissue damage and PUFA cytotoxicity (lactate dehydrogenase assay). Epidermal and dermal lipid profiles were assessed by gas chromatography and liquid chromatography coupled to tandem mass spectrometry. Primary keratinocytes were treated with fatty acids and various lipid mediators for 48h. Their effect was determined by the scratch assay and transepithelial electrical resistance. UVR upregulated COX-2 in HaCaT and primary epidermal keratinocytes, but did not affect mPGES-1 and 15-PGDH protein expression. UVR upregulated COX-2 and mPGES-1 in 46BR.1N fibroblasts but had no effect on 15-PGDH expression. The same UVR dose did not alter the expression of COX-2, mPGES-1 and 15-PGDH in primary dermal fibroblasts. Only EPA attenuated COX-2 expression in HaCaT and primary keratinocytes and either EPA or DHA had any effect in 46BR.1N and primary fibroblasts. Skin explants showed initial post-biopsy tissue damage. EPA and DHA supplementation augmented cellular levels of the corresponding fatty acids in both epidermis and dermis to a different extent. Increased uptake of DHA in the dermis was accompanied by reduced arachidonic acid levels. EPA treatment stimulated the production of PGE3 and various HEPE in epidermis, while DHA treatment caused high levels of HDHA species in dermis. N-3 PUFA and their derivatives delayed wound healing, cell migration and epidermal barrier permeability, while n-6 PUFA lipids showed the opposite effect. Overall, these findings suggest that EPA and DHA differently affect skin cells and skin, with EPA preference in epidermis and DHA in the dermis. These results highlight the importance of differential skin responses that could be important in skin health and disease.