The discovery of Notch in Drosophila melanogaster nearly a century ago opened the door to an ever-widening understanding of cellular processes that are controlled or influenced by Notch signalling. As would be expected with such a pleiotropic pathway, the deregulation of Notch signalling leads to several pathological conditions, including cancer. A role for Notch is well established in haematological malignancies, and more recent studies have provided evidence for the importance of Notch activity in solid tumours. As it is thought to act as an oncogene in some cancers but as a tumour suppressor in others, the role of Notch in solid tumours seems to be highly context dependent.

Over the past 100 years, changes in the food supply in Western nations have resulted in alterations in dietary fatty acid consumption, leading to a dramatic increase in the ratio of omega-6 (6) to 3 polyunsaturated fatty acids (PUFA) in circulation and in tissues. Increased 6/3 ratios are hypothesized to increase inflammatory mediator production, leading to higher incidence of inflammatory diseases, and may impact inflammatory gene expression. To determine the effect of reducing the 6/3 ratio on expression of inflammatory pathway genes in mononuclear cells, healthy humans were placed on a controlled diet for 1 week, then given fish oil and borage oil for an additional 4 weeks. Serum and neutrophil fatty acid composition and ex vivo leukotriene B 4 production from stimulated neutrophils were measured at the start and end of the supplementation period and after a 2-week washout. RNA was isolated from mononuclear cells and expression of PI3K, Akt, NFB, and inflammatory cytokines was measured by real-time PCR. A marked increase was seen in serum and neutrophil levels of long-chain 3 PUFA concomitant with a reduction in the 6/3 PUFA ratio (40%). The ex vivo capacity of stimulated neutrophils to produce leukotriene B 4 was decreased by 31%. Expression of PI3K␣ and PI3K␥ and the quantity of PI3K␣ protein in mononuclear cells was reduced after supplementation, as was the expression of several proinflammatory cytokines. These data reveal that PUFA may exert their clinical effects via their capacity to regulate the expression of signal transduction genes and genes for proinflammatory cytokines.Since the beginning of the 20th century, the fatty acid composition of complex lipids (such as triglycerides) in Western diets has changed dramatically, largely due to a marked increase in the consumption of omega-6 (6) polyunsaturated fatty acids (PUFA) 2 and a concomitant decrease in the consumption of omega-3 (3) PUFA (1, 2). The increased ingestion of 6 PUFA is due in large part to growth in the production and consumption of vegetable oils, beef, pork, and poultry and has been exacerbated by changes in livestock husbandry and feeding practices (3). This together with a reduced consumption of wild, fatty fish containing high concentrations of 3 PUFA has resulted in lower 3 intake and in 6/3 ratios in the United States diet of greater than 10:1. Anthropological evidence suggests that our hunter-gatherer ancestors maintained a ratio closer to 2:1 for ϳ100,000 generations (3, 4). This dietary change is postulated to enhance circulating and cellular pro-inflammatory mediators (eicosanoids and cytokines) and reduce anti-inflammatory mediators, resulting in an overall increase in systemic inflammation and a higher incidence of allergic and inflammatory disease including asthma, allergies, diabetes, cardiovascular disease, and arthritis.However, despite 50 years of research supporting the efficacy of long chain PUFA, such as eicosapentaenoic acid (EPA, 20:5, 3) and docosahexaenoic acid (DHA, 20:6, 3) in treating inflammatory diseases, a...

No abstract