Plant polyphenols are reported to have bioactive properties, which may be used for protection against diseases. Therefore, the aim of this research was to investigate the bioactive activities of a pomegranate tannin polyphenol compound, punicalagin. In particular, the antioxidant, antihypertensive and anticancer mechanisms were investigated. Punicalagin was found III pomegranate husk but not in pomegranate juice when analysed by HPLC and LC-MS. Antioxidant mechanisms involved hydrogen peroxide scavenging, ferrous chelating and reducing ability. Higher hydrogen peroxide scavenging activity was achieved by 0.1 mg/ml from both punicalagin and pomegranate juice when compared with butylated hydroxytoluene (BHT) or trolox (p :S0.05). Punicalagin and pomegranate juice exhibited ferrous chelating ability significantly lower than Ethylenediaminetetraacetic acid. Cell toxicity induced by tert-butylhydroperoxide (3 mM) was significantly inhibited by punicalagin (5 and 10 !!M) in Caco-2 cells; these results were confinned by cell morphology. Punicalagin protection was achieved by inhibiting cellular reactive oxygen species (ROS) as well as malondialdehyde levels. Glutathione level was significantly increased in stressed cells pretreated with both concentration of punicalagin, indicating good antioxidant activity for punicalagin. Punicalagin (1-60 !!M) increased nitric oxide production in endothelial cells (EA.hy926) through decreased ROS levels and increased endothelial nitric oxide synthase enzyme (eNOS) activation. Activation of eNOS enzyme was achieved by an II - increase of cellular calcium concentration. At the same examined concentration of punicalagin (1-60 f-tM), the activity of angiotensin converting enzyme (ACE) was significantly inhibited. The dual action of punicalagin as nitric oxide synthase inducer and ACE inhibitor showed antihypertensive effect. Punicalagin (50 and 75 f-tM) showed toxic effects on the colon cancer cell line (Caco-2) but not on a normal colon cell line (HCEC); both results were confinned by morphological studies. In the presence of punicalagin, cytoplasmic ROS production decreased, indicating antioxidant activity whereas superoxide radicals released from mitochondria increased due to mitochondrial dysfunction. Annexin V and caspase family (caspase 9, 8 and 3) activation confinned that cell death occurred via apoptosis pathway by both concentrations of punicalagin. The cell cycle was attested by punicalagin in the G liS-phase at the concentrations tested. The above findings indicating that punicalagin has antioxidant, antihypertensive and anticarcinogenic activity.

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Cardiovascular disease rates (CVD) are high in the UK, particularly in men. National surveys report a dietary imbalance of fats and antioxidant micronutrients, which may adversely influence blood fatty acid profile and risk for CVD. We investigated relationships between saturated and unsaturated dietary fat, and antioxidant (retinol, alpha-tocopherol, beta-carotene, iron, zinc, selenium, magnesium and copper) intakes, and blood glucose, lipoproteins and cell membrane fatty acids in a homogenous group of educated, healthy Caucasian men and women. Volunteers (20 to 50 years, men 52, women 52) were recruited from staff and students of London Metropolitan University. Following correction for under-reporting 40 women and 31 men were included in the dietary analysis. Dietary intake, body composition, blood pressure, fasting blood glucose and lipids, and fatty acid composition of plasma and blood cell membranes (red blood cells, and platelets) were analysed. The men consumed more saturated fat (11.0 vs 9.8 %energy intake, p<0.05), and exhibited elevated glucose (5.41 vs 4.81 mmol/I, p<O.001), systolic blood pressure (126.4 vs 112.0 mm/Hg, p<0.001), triglycerides (1.22 vs 0.98 mmol/I, p<0.05), LDL- cholesterol (2.90 vs 2.55 mmolll, p<0.05), LDL:HDL (2.09 vs 1.44, p<0.001) and lower HDL-cholesterol (1.47 vs 1.87 mmolll, p< 0.001) levels compared to the women, despite higher total body and trunk fat in the women (26.5 vs 15.6 %, and 23.3 vs 16.8 %, p<0.001 for both). In addition, the men consumed more zinc (11.7 vs 8.8 mg/d, p<0.001), and selenium (84 vs 54 f.Jg/d, p<0.01), while women consumed more beta-carotene (2.9 vs 2.3 mg/d, p<0.05), and vitamin C (138 vs 108 mg/d, p<0.05). In addition, gender comparisons of micronutrient densities demonstrated higher copper, magnesium, iron and vitamin E densities in the women's' diets, indicating more balanced nutritional intakes. Despite these findings no differences were found in plasma micronutrient levels (copper, iron, magnesium, retinol and alpha-tocopherol) between the men and women. Furthermore, despite similar total n-3 intakes, women displayed higher proportions of DHA in plasma (PC: 2.8 vs 3.2 area%, p<0.01), RBCs (PE: 7.8 vs 6.8 area%, p<0.01), and in platelets (PC: 1.19 vs 1.05 area%, p<0.05; PE: 3.62 vs 3.21 area%, p<0.05), and a greater DHA: DPAn-3 (PC: 1.91 vs 1.67 area%, <0.05; PE: 1.15 vs 0.98 area%, p<0.05) compared to the men, suggesting enhanced bioconversion rates in this age group of women. In addition, proportionally, Itrwer total n-6 levels and n-6:n-3 fatty acids were found in the platelets of women (PC: 23.9 vs 25.0 area%, p<0.01; 10.0 vs 11.7, p<0.05) providing further evidence for greater cardio- protection in these women of child-bearing age. Further analysis suggested that in the women DHA levels appeared to be unrelated to dietary intake, while in contrast in the men, there appeared to be a greater reliance on pre-formed dietary intake, and LDI cholesterol was more responsive to the lowering effect of dietary n-6 fat (Beta -0.382, R2 0.214, p<0.01). In contrast, many associations were found between dietary antioxidants, in particular zinc, and plasma and RBC EPA and DHA levels especially in the women. The data of this study indicate gender-related differences in fat and micronutrient intakes, and associations with lipoproteins and blood fatty acids. Further research should investigate whether requirements for dietary LC-PUFAs particularly DHA differ for men and women. 11

It is widely accepted that diet strongly influences the incidence and onset of both cardiovascular diseases and neurodegeneration. Recently, phytochemical-rich foods, particularly those rich in flavonoids, such as blueberries, green tea and cocoa, have been shown to have a positive impact on memory and learning and cognitive function in both animals and humans. The mechanisms by which flavonoids exert these actions on cognitive performance are starting to emerge with evidence suggesting that they may modulate the activation status of neuronal receptors, signaling proteins and gene expression in the hippocampus. In the present Thesis we further explore the mechanisms by which flavonoids, present in blueberry, affect memory and learning in both young and aged rodents and relate such changes in the brain with behavioural cognitive outcomes. We show for the first time that pure flavonoids present in blueberry, particularly the flavanol monomers (- )-epicatechin and catechin and anthocyanins, are capable of mediating improvements in spatial memory in aged animals when dosed at the same levels they are found within the blueberry. This data suggests that flavonoids are the likely causal agents that mediate the cognitive effects of blueberry in vivo. We also show a positive impact of blueberry supplementation on spatial memory in young rodents in two separate experiments using well-establlshed behavioural paradigms. Mostly importantly we found that chronic blueberry intervention causes an up-regulation of hippocampal BDNF at protein level and at mRNA level in both young and aged animals, reinforcing the importance of this neurotrophin in the blueberry- induced learning and memory improvements. A more detailed analysis of the mechanisms underlying the impact of flavonoid-rich blueberries on memory revealed an increase in PSA-NCAM positive neurons in the dentate gyrus which is known to mediate synaptic transmission and neuronal remodeling. Further increases in NR2B-containing NMDR receptors in the hippocampus correlate with up-regulation with PSA-NCAM, suggesting an enhancement of synaptic plasticity, likely to be driven by an increase in glutamate signaling. As such, these changes seem to be mediated by central signaling pathways utilized in learning processes, notably ERK-CREB-BDNF and Akt-mTOR-ARC. Overall, our results provide further support for the impact of flavonoid-rich blueberries on learning performance in aged rodents as well as in young healthy rodents, suggesting a potential mechanism by which flavonoids act in the brain.

Tocopherols and tocotrienols are very important antioxidants in biological systems. This thesis describes a study of the effect of structure and environmental conditions on the stability and antioxidant activity of tocopherols and tocotrienols in lipoxygenasecatalysed oxidation and in heated oils at elevated temperatures. In the first phase of the project, the mechanism by which α-, β- ,γ-, and δ-tocopherol homologues inhibit lipoxygenase catalysed oxidation of linoleic acid was studied. Primary oxidation products formed during lipoxygenase catalysed oxidation were monitored by determination of conjugated diene formation at 234 nm.

B-vitamin deficiency may contribute to age-related diseases. Low/deficient vitamin B 12 status is of particular concern in older people despite the fact that intakes of B 12 typically far exceed current recommendations. Pernicious anaemia accounts for a very small proportion of low/deficient status, however, a much more prevalent problem is food-bound vitamin B 12 malabsorption. Proton pump inhibitor [PPI] drugs are acid suppressant drugs which reduce gastric acid secretion [hypochlorhydria] and could thus potentially reduce the absorption of food-bound vitamin B 12. Using an experimental model of hypochlorhydria, the current results showed no evidence of vitamin B 12 depletion as a result of short-term PPI administration. Long-term PPI usage was however shown to be associated with an increased risk of vitamin B 12 deficiency but this appeared to be alleviated by the regular consumption of foods fortified with the vitamin, with a 19% prevalence of vitamin B 12 deficiency found in long-term PPI users who were non-consumers compared to a 2% prevalence in consumers. Overall the results highlight the importance of fortified food consumption in maintaining vitamin B 12 status, particularly in those at risk of food bound malabsorption owing to PPI usage. This thesis also demonstrated that low dose vitamin B 12 (1μg/d) supplementation can significantly increase vitamin B 12 status both in healthy people and in long-term PPl users. Of note, the investigation of vitamin B 12 biomarker responses to vitamin B 12 depletion and repletion study presented in this thesis indicated that holotranscobalamin (holoTC) was a more sensitive biomarker of vitamin B 12 status and responded quicker to changes in vitamin B 12 status than the more conventional biomarker, serum total B 12. One of the most important findings of this thesis was that low vitamin B6 status was associated with a 6-fold increased risk of cognitive decline in a cohort of healthy older adults investigated over a 4 year period. This largely overlooked B- vitamin may have an important role to play in maintenance of cognitive function in healthy ageing.

Les produits déshydratés permettent d’optimiser la conservation et le transport des aliments. Les poudres alimentaires distribuées au consommateur affichent des garanties nutritionnelles en termes d’apports qualitatif et quantitatif. Cependant, l’apport nutritionnel du produit après reconstitution et cuisson, n’est pas garanti. Ce travail se concentre sur l’évaluation des pertes en vitamines dues aux procédés de transformation alimentaire en lien avec l’effet de la matrice alimentaire. Ces pertes mesurées après le traitement thermique ne sont pas négligeables, rendant l’encapsulation nécessaire pour répondre à l’objectif de la thèse de garantir une teneur en vitamines suffisante après reconstitution et traitement thermique du produit alimentaire déshydraté. Différentes matrices ont été testées à l’échelle laboratoire et industrielle. Parmi ces matrices, certaines comme les protéines laitières et l’amidon se sont avérées très intéressants et ont permis la préservation de la vitamine C du traitement thermique. Pour finaliser l’étude, il a été indispensable de prendre en compte le stockage des poudres de la vitamine C encapsulée avant et après leur commercialisation. Pour assurer leur teneur suffisante en vitamine C lors ce stockage, un vieillissement accéléré a été effectué. Cette thèse a permis d’apporter des réponses concrètes au problème industriel posé, qui était de garantir la teneur en vitamine C des produits commercialisés après reconstitution et traitement thermique / Dehydrated products make it possible to optimize the storage and transport of food products. Food powder mixes distributed to the consumer display nutritional guarantees in terms of qualitative and quantitative inputs. However, the nutritional value of the product after reconstitution and cooking, is not guaranteed. This PhD work focuses on the evaluation of vitamins losses due to food processing in relation to the effect of the food matrix. Losses measured after the heat treatment were not negligible, making the encapsulation necessary to meet the objective of the thesis to guarantee a sufficient vitamins content after reconstitution and heat treatment of the dehydrated food product. Different matrices have been tested at the laboratory scale and industrial scales. Some of these matrices, such as dairy proteins and starch, have proved to be very interesting and allowed the preservation of vitamin C during heat treatment. To finalize the study, it was essential to take into account that the vitamin C-encapsulating powders will be stored before and after their distribution. To ensure that they maintain a sufficient vitamin C content during storage, accelerated aging has been carried out. Thus this thesis made it possible to provide concrete answers to the posed industrial problem, which was to guarantee the vitamin C content of the commercial products after reconstitution and heat treatment