Graduation date: 2006

Diferents estudis assenyalen que el consum de peix, a través dels àcids grassos poliinsaturats omega-3 (AGPI omega-3), pot prevenir malalties vasculars lligades a l'aterosclerosi. Els AGPI omega -3 són altament insaturats, la qual cosa els fa especialment susceptibles a l'atac oxidatiu. Com que la lipoperoxidació de les lipoproteïnes de baixa densitat (LDL) és un dels esdeveniments clau en les etapes inicials de la formació de la placa d'ateroma, això faria d'una suplementació amb oli de peix de la dieta un factor potencialment pro-aterogènic. Així doncs, hi ha d'haver altres mecanismes que contrarestin l'efecte pro-oxidant dels AGPI omega-3 i que expliquin les seves propietats antiaterogèniques. A partir dels AGPI omega-6 i omega-3, se sintetitzen dues sèries diferents d'eicosanoids. Generalment, els primers presenten una activitat biològica més gran que els segons. Les dues sèries d'eicosanoids constitueixen un element clau en les accions diferenciades dels AGPI omega-3 respecte dels AGPI omega -6. Entre les accions del AGPI omega -3, i pel que fa a l'aterogènesi, hipotetitzem la modulació de la producció de radicals lliures com l'òxid nítric (·NO), sintetitzat per l'enzim eNOS en l'endoteli vascular, i d'efecte relaxador, i l'anió superòxid, d'efecte vasoconstrictor.Per tal d'estudiar els efectes d'una suplementació amb AGPI omega-6 i amb AGPI omega -3 en vasos i en lipoproteïnes, s'alimentaren rates Sprague-Dawley, amb una dieta rica o bé en oli de blat de moro (5%, ric en AGPI omega -6), o bé en oli de peix (5%, ric en AGPI omega-3) durant 8 setmanes. Part dels animals, a més, reberen una suplementació addicional de L-arginina lliure, substrat de l'eNOS. Després del període d'alimentació, els animals eren sacrificats i se n'extreia l'aorta (per fer estudis vasculars) i la sang (per obtenir-ne les lipoproteïnes de molt baixa densitat (VLDL) i les LDL).Els estudis en bany d'òrgans van permetre d'observar un augment en la relaxació induïda per acetilcolina i mediada per ·NO en les rates suplementades amb oli de peix. L'augment d'aquestes relaxacions no era degut ni a una menor producció de superòxid (O2·-, principal agent limitador de la biodisponibilitat vascular de ·NO), ni a una major resposta del vas al ·NO (no hi havia diferències en les relaxacions induïdes per nitroprussiat sòdic, un donador de ·NO).D'altra banda, també augmentava, en les rates suplementades amb oli de peix, la producció basal de ·NO (avaluada per ressonància de spin electrònic), fenomen vinculat, a més, a l'estimulació de l'expressió del ARNm i de la proteïna d'eNOS. Això s'acompanyava d'una davallada del contingut de L-arginina lliure del teixit i d'un augment del GMPc. Quant a la suplementació de L-arginina en les dietes, aquesta produïa també un augment, en tots dos tipus d'olis, de la producció vascular de ·NO.Pel que fa a la fracció de VLDL+LDL, no s'hi observaven canvis deguts a la dieta en la mobilitat electroforètica, que és un indicador del grau d'oxidació nadiu d'aquestes. En canvi, la suplementació amb oli de peix davallava les reserves d'alfa-tocoferol de les lipoproteïnes. En consonància amb això, davant un atac oxidatiu ex vivo induït per Cu2+, les lipoproteïnes de les rates suplementades amb oli de peix, iniciaven l'oxidació abans, però alhora s'hi propagava menys ràpidament i el nivell màxim de diens conjugats era més baix.L'augment de la producció vascular de ·NO generat per la suplementació amb oli de peix, és un mecanisme potencialment antiaterogènic, a través del manteniment del to vascular mitjançant l'activitat vasorelaxadora del ·NO. A banda d'això, el ·NO, d'acord amb diversos estudis in vitro, actua com a antioxidant en lipoproteïnes que podria interferir en la propagació de l'oxidació in vivo i explicar la paradoxa de l'oli de peix en la prevenció de l'aterosclerosi.

Includes bibliographical references (leaves 237-257). / xx, 257 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Investigates the mechanisms underlying the antiarrhythmic effects of omega-3 polyunsaturated fatty acids using adult rat ventricular cardiac myocytes. / Thesis (Ph.D.)--Adelaide University, Dept. of Physiology, 2001

[Truncated abstract] Increased incidence of hypertension, insulin resistance, obesity and dyslipidemia, collectively referred to as the metabolic syndrome, has been linked to low birth weight, an indicator of a poor fetal environment. This association reflects developmental programming, a process by which organ systems are affected during early development such that disease states are more likely to emerge in adult life. Fetal glucocorticoid overexposure is thought to be a key factor that mediates developmental programming. Accordingly, maternal treatment with the synthetic glucocorticoid dexamethasone retards fetal growth and leads to delayed puberty, hypertension, hyperinsulinemia, and hyperleptinemia, either with or without increased adiposity, in adult offspring. Importantly, the postnatal environment can either amplify or attenuate the long-term outcome of developmental programming. The focus of this thesis was whether adverse developmental programming outcomes can be attenuated by the postnatal environment and thus provide therapeutic potential. Specifically, the effects of a postnatal diet rich in omega-3 fatty acids on glucocorticoid-induced developmental programming outcomes was investigated. ... The adipocyte phenotype was examined in Study 6, with hyperleptinaemia evident in offspring at 6 and 12 months of age in dexamethasone-exposed animals on a standard omega-3 diet, but this effect was prevented by a high omega-3 diet. The pattern of plasma leptin was paralleled by changes in leptin mRNA in retroperitoneal fat. Similarly, plasma levels of the inflammatory markers IL-6 and IL-1β were upregulated by prenatal glucocorticoid exposure and these were attenuated by postnatal dietary omega-3 fatty acids. Overall, omega-3 ingestion reduced adiposity, as indicated by measures of body composition. In conclusion, the studies presented in this thesis demonstrate for the first time that many of the detrimental effects of excess glucocorticoid exposure in utero on the adult phenotype can be attenuated by a postnatal diet rich in omega-3 fatty acids. This beneficial effect of omega-3 fatty acids was associated with a reversal of some (e.g. adiposal leptin) but not all (e.g. renal GR) 'programmed' changes in gene expression. These findings raise the possibility that dietary supplementation with omega-3 fatty acids may provide a viable therapeutic option for preventing and/or reducing adverse programming outcomes in humans.

Thesis (M.S.)--Oregon State University, 2007-12-20. / Printout. Includes bibliographical references (leaves 121-127). Also available on the World Wide Web.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 5 uppsatser.

Thesis (M.S.)--West Virginia University, 2009. / Title from document title page. Document formatted into pages; contains vii, 42 p. : ill. Includes abstract. Includes bibliographical references (p. 29-35).

Thesis (Ph.D.)--Memorial University of Newfoundland, 1997. / Restricted until December 2000. Bibliography: leaves [252]-282.

Busca enriquecer la carne de cuy (Cavia porcellus) con ácidos grasos omega-3, EPA y DHA, mediante el uso de aceite crudo de pescado como fuente de ⍵-3. Se utilizaron 90 cuyes machos raza Perú, con una edad promedio de 21 días de edad y con un peso inicial de 350 g. Los cuyes se asignaron al azar a tres tratamientos con quince repeticiones (pozas) de dos cuyes cada una. Los tratamientos fueron: dieta control, dieta suplementada con 1.0% de aceite crudo de pescado y dieta suplementada con 2.0% de aceite crudo de pescado. La fase experimental tuvo una duración de 29 días. La carne de cuyes alimentados con la dieta con aceite crudo de pescado al 1% presentó 0.28 % de ⍵-3 de cadena larga (0.1% ácido eicosapentaenoico [EPA] + 0.18% ácido docosahexaenoico [DHA]) y aquella con dieta con aceite de pescado al 2% alcanzó 0.65% de ⍵-3 (0.18% EPA + 0.47% DHA). Las carnes de cuyes alimentados con la dieta control no presentaron ⍵-3 de cadena larga EPA/DHA. Asimismo, la carne de cuyes alimentados con la dieta con 1% de aceite crudo de pescado exhibió el más alto contenido de ácidos grasos poliinsaturados (44.96%) y el menor de ácidos grasos monoinsaturados (25.12%) y de ácidos grasos saturados (29.19%), respecto a la dieta suplementada con 2% de aceite crudo de pescado. Se concluye que las dietas suplementadas con aceite de pescado produjo en la carne de cuy una retención de ácidos grasos ⍵-3 EPA y DHA. / Tesis

Chronic inflammation has been linked to cancer. Prostaglandin E2 (PGE2) is the most pro-inflammatory lipid and one of the downstream products of 2 isoforms of cyclooxygenase (COX) enzymes: COX-1 and COX-2. Although both COX isoforms have similar structure and function, they are encoded by different genes and show distinct expression patterns. COX-1 is expressed in most cells and tissues and remains constant under most physiologic conditions to play a housekeeping role whereas the COX-2 form is inducible and usually only expressed in response to various inflammatory stimuli. COX enzymes may be involved in both tumor establishment and maintenance of existing tumors. PGE2 exerts its effects on target cells by coupling to four subtypes of receptors which have been classified as EP1-4. Ovarian cancer is the most lethal gynecological malignancy and mainly occurs in older women. Prevention may be the best approach to reduce ovarian cancer. Ovarian cancer is the fifth leading cause of cancer death among women and the most lethal gynecological malignancy. There are at least 3 well established risk factors for ovarian cancer: age, family history and environmental factors. Ovarian cancer is mainly seen in older women when their ovaries are not reproductively functional. Close to half of the women with ovarian cancer (48%) are in the age group of 65 or older. Epidemiological and preclinical studies indicate that increased dietary intake of omega-3 fatty acids (OM-3FAs) reduces the incidence and growth of various cancers. Thus, increasing the consumption of OM-3FAs may be a nontoxic way to prevent or suppress ovarian cancer. Flaxseed is the richest vegetable source of omega-3 fatty acids which may be effective in the prevention of ovarian cancer. Fish oil is a source of OM-3FAs which may be effective in prevention of ovarian cancer. The main OM-6FA, Linoleic Acid (LA), is a direct precursor of the Arachidonic Acid (AA). Alpha-linolenic acid (ALA) is the main OM-3FA found in flax oil, whereas eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the OM-3FAs in fish oil. ALA is elongated to form EPA and DHA in the intestine. Celecoxib is a non-steroidal anti-inflammatory (NSAID) drug that selectively inhibits COX-2. There are evidences showing that Celecoxib has some anti-cancer properties. Progress in the treatment and prevention of ovarian cancer has been hampered due to the lack of an appropriate animal model and absence of effective chemo-prevention strategies. The domestic hens spontaneously develop ovarian adenocarcinomas that share similar histological appearance and symptoms such as ascites and metastasis with humans. Our first objective was to investigate the effect of flaxseed supplementation for one year on ovarian cancer and correlate its effects to expression of COX enzymes and concentrations of prostaglandins. White Leghorn hens were fed 10% flaxseed-enriched or standard diet for one year. The severity of ovarian cancer was determined by gross pathology and histology. COX-1 and COX-2 localization and protein and mRNA expression and PGE2 and PGE3 concentrations in ovaries were measured by Immunohistochemistry, western blot, quantitative real-time PCR and LC-MS-MS, respectively. The results demonstrated a significant reduction in late stage ovarian tumors in the flaxseed-fed hens compared with the control diet-fed hens. In correlation with decreased ovarian cancer severity, concentrations of PGE2 and expression of COX-2 were diminished in ovaries of flaxseed-fed hens. PGE3 concentrations were below the level of detection. The results demonstrated that in normal ovaries, COX-1 was localized to the granulosa cell layer surrounding the follicles and ovarian surface epithelium (OSE) whereas COX-2 protein was localized to the granulosa cell layer in the follicle. Extensive COX-1 and COX-2 protein expression was found throughout the ovarian carcinoma. Our findings suggest that the flaxseed-mediated reduction in the severity of ovarian cancer in hens is correlated to the reduction in PGE2 in the ovaries of flaxseed-fed hens. Since no effect on ovarian cancer incidence was detected after feeding the 2. 5 year old hens with 10% flaxseed for 1 year, we designed a long-term study using 6 month old hens. Our objectives were: 1) to examine the expression of COX enzymes and PGE2 levels in ovaries and correlate them to ovarian cancer and aging 2) to determine if long-term consumption of a flaxseed enriched diet decreases ovarian cancer severity and incidence in the laying hen and to investigate its potential correlation with the expression of COX enzymes and PGE2 concentration. White Leghorn hens were fed 10% flaxseed-enriched or standard diet for 4 years. The severity and incidence of ovarian cancer were determined by gross pathology and histology. COX-1 and COX-2 protein and mRNA expression and PGE2 concentrations in ovaries were measured by western blot, quantitative real-time PCR and ELISA, respectively. Our results indicated an increase in ovarian cancer incidence and expression of both COX enzymes in ovaries of older hens. In correlation with ovarian cancer incidence and COX enzymes expression, PGE2 concentrations were elevated with age. Ovaries with tumor had elevated COX-1 expression and PGE2 concentration compared to normal ovaries. Our findings suggest that the up-regulation of COX enzymes with age is the main contributing factor in the age associated increase in PGE2. Furthermore, elevated PGE2 in ovaries of hens concomitant with age suggests its important role in early stages of ovarian carcinogenesis. The results demonstrated that there was a reduction in ovarian cancer severity and incidence in hens fed flaxseed diet. In correlation with decreased ovarian cancer severity and incidence, concentration of PGE2 and expression of COX-2 were diminished in ovaries of hens fed flaxseed. Our findings suggest that the lower levels of COX-2 and PGE2 are the main contributing factors in the chemo-suppressive role of long-term flaxseed consumption in ovarian cancer in laying hens. These findings may provide the basis for clinical trials of dietary intervention targeting prostaglandin biosynthesis for the prevention and treatment of ovarian cancer. Based on our previous findings, targeting COX expression and prostaglandin biosynthesis by dietary intervention using OM-3FAs and selective COX inhibitor can be an effective approach to prevent or suppress ovarian cancer. Thus, we conducted a series of studies to assess effect of fish oil, flax oil, Celecoxib, fish oil and Celecoxib combined or flax oil and Celecoxib combined on COX-1 and COX-2 expression, PGE2 concentrations, proliferation and apoptosis in normal and cancerous ovaries of laying hens. This study had not been performed in hens before, thus the first step was to find the optimum doses. In order to do so, we utilized one year old hens, divided them to groups of 6 hens, and fed them different doses of fish oil (50, 100, 175, 375 and 700 mg/kg), flax oil (100, 250, 500, 1000 and 1500 mg/kg) or Celecoxib (35, 65 and 100 mg/kg) for three weeks. The OM3-FAs andomega-6 fatty acids contents of egg yolks were determined by gas chromatography. Proliferation, apoptosis,COX-1, COX-2 and prostaglandin receptor subtype 4 (EP4) protein and mRNA expression and PGE2 concentration in ovaries were measured by PCNA, TUNEL, western blot, quantitative real-time qPCR and ELISA, respectively. The results indicated that 100 mg/kg fish oil was the most effective dose in reducing COX enzymes and PGE2, and increased apoptosis and reduced proliferation in ovaries. The lower doses of fish oil incorporated more OM-3FAs into yolks, reduced OM-6FAs and increased the egg laying frequency but did not affect EP4 expression. Unlike fish oil, the highest dose of flax oil (1500 mg/kg) caused the most significant reduction in COX expression and PGE2 concentration. Celecoxib was not perfectly selective in targeting COX-2, however, treating the hens with 65 mg/kg Celecoxib resulted in the most significant amelioration of PGE2 levels in ovaries. Using the optimum doses of fish oil, flax oil and Celecoxib, we aimed to investigate if these components can alter ovarian cancer end-points in normal and cancerous hen ovaries. There is an adverse relation between ovulation and health of ovaries. Thus, 3-4 year old hens were monitored for egg laying frequency and the hens with the least ovulation rate were selected for health assessment. The hens presenting poor health were scanned using ultrasound and if tumor mass and/or ascites were detected, they were chosen for this study. The hens with normal and cancerous ovaries were divided to groups and were fed fish oil, flax oil, Celecoxib, fish oil and Celecoxib combined, or flax oil and Celecoxib combined for 42 days. The results showed that fish oil and flax oil increased the incorporation of OM-3FAs into egg yolks in both normal and cancerous ovaries of hens. Fish oil reduced COX-1 and COX-2 in normal and cancerous ovaries. Fish oil, flax oil and Celecoxib reduced the COX-2 expression in ovaries. Combination of fish oil and Celecoxib and flax oil and Celecoxib decreased COX and PGE2 more than each of these treatments alone. The cancerous ovaries of hens treated with fish oil, flax oil, Celecoxib, and flax oil and Celecoxib combined increased the percentage of apoptotic cells compared to cancerous ovaries of control hens. The cancerous ovaries of hens treated with fish oil and Celecoxib had the highest number of apoptotic cells indicating that the combination of fish oil and Celecoxib is more effective than fish oil or Celecoxib alone. To our knowledge the present study provides the first insight into the efficacy of fish oil, flax oil, Celecoxib, alone or combined on the reduction of COX enzyme expression, PGE2 concentration and apoptosis in the normal and cancerous ovaries and further demonstrates the utility of the hen model for ovarian cancer. Our studies provided new insight into the potential mechanism of action of flaxseed, fish oil, flax oil and Celecoxib in the reduction of ovarian cancer and will establish the foundation for clinical trials to test the efficacy of dietary intervention for the prevention and suppression of ovarian cancer in women.