Apolipoprotein E gene polymorphism modifies fasting total cholesterol concentrations in response to replacement of dietary saturated with monounsaturated fatty acids in adults at moderate cardiovascular disease risk

Consumption of ≤10% total energy from fat as saturated fatty acids (SFA) is recommended for cardiovascular disease risk reduction in the UK; however there is no clear guidance on the optimum replacement nutrient. Lipid-associated single-nucleotide polymorphisms (SNPs) have been shown to modify the lipid responses to dietary fat interventions. Hence, we performed a retrospective analysis in 120 participants from the Dietary Intervention and VAScular function (DIVAS) study to investigate whether lipoprotein lipase (LPL) and apolipoprotein E (APOE) SNPs modify the fasting lipid response to replacement of SFA with monounsaturated (MUFA) or n-6 polyunsaturated (PUFA) fatty acids. The DIVAS study was a randomized, single-blinded, parallel dietary intervention study performed in adults with a moderate cardiovascular risk who received one of three isoenergetic diets rich in SFA, MUFA or n-6 PUFA for 16 weeks. After the 16-week intervention, a significant diet-gene interaction was observed for changes in fasting total cholesterol (P = 0.001). For the APOE SNP rs1064725, only TT homozygotes showed a significant reduction in total cholesterol after the MUFA diet (n = 33; -0.71 ± 1.88 mmol/l) compared to the SFA (n = 38; 0.34 ± 0.55 mmol/l) or n-6 PUFA diets (n = 37; -0.08 ± 0.73 mmol/l) (P = 0.004). None of the interactions were statistically significant for the other SNPs. In summary, our findings have demonstrated a greater sensitivity of the APOE SNP rs1064725 to dietary fat composition, with a total cholesterol lowering effect observed following substitution of SFA with MUFA but not n-6 PUFA. Further large intervention studies incorporating prospective genotyping are required to confirm or refute our findings. The trial was registered at www.clinicaltrials.gov as NCT01478958

Impact of Flavonoids on Cellular and Molecular Mechanisms Underlying Age-Related Cognitive Decline and Neurodegeneration

Purpose of Review This review summarises the most recent evidence regarding the effects of dietary flavonoids on age-related cognitive decline and neurodegenerative diseases. Recent Findings Recent evidence indicates that plant-derived flavonoids may exert powerful actions on mammalian cognition and protect against the development of age-related cognitive decline and pathological neurodegeneration. The neuroprotective effects of flavonoids have been suggested to be due to interactions with the cellular and molecular architecture of brain regions responsible for memory. Summary Mechanisms for the beneficial effects of flavonoids on age-related cognitive decline and dementia are discussed, including modulating signalling pathways critical in controlling synaptic plasticity, reducing neuroinflammation, promoting vascular effects capable of stimulating new nerve cell growth in the hippocampus, bidirectional interactions with gut microbiota and attenuating the extracellular accumulation of pathological proteins. These processes are known to be important in maintaining optimal neuronal function and preventing age-related cognitive decline and neurodegeneration

Neuroinflammation and its modulation by flavonoids

There is increasing evidence to suggest that neuroinflammatory processes contribute to the cascade of events that lead to the progressive neuronal damage observed in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Therefore, treatment regimes aimed at modulating neuroinflammatory processes may act to slow the progression of these debilitating brain disorders. Recently, a group of dietary polyphenols known as flavonoids have been shown to exert neuroprotective effects in vivo and in neuronal cell models. In this review we discuss the evidence relating to the modulation of neuroinflammation by flavonoids. We highlight the evidence which suggests their mechanism of action involves: 1) attenuation of the release of cytokines, such as interleukin-1beta (IL-1beta and tumor necrosis factor-alpha (TNF-alpha); 2) an inhibitory action against inducible nitric oxide synthase (iNOS) induction and subsequent nitric oxide (NO(*)) production; 3) inhibition of the activation of NADPH oxidase and subsequent reactive oxygen species generation; 4) a capacity to down-regulate the activity of pro-inflammatory transcription factors such as nuclear factor-kappaB (NF-kappaB); and 5) the potential to modulate signalling pathways such as mitogen-activated protein kinase (MAPK) cascade. We also consider the potential of these dietary compounds to represent novel therapeutic agents by considering their metabolism in the body and their ability to access the brain via the blood brain barrier. Finally, we discuss future areas of study which are necessary before dietary flavonoids can be established as therapeutic agents against neuroinflammation

The ability of dietary polyphenols to protect against endogenously-formed neurotoxins

Parkinson disease is characterized by a progressive and selective loss of dopaminergic neurons in the substantia nigra. Although the mechanisms by which these neurons degenerate is unclear, accumulating evidence suggests that endogenously formed 5-S-cysteinyl-dopamine (CysDA) conjugates, formed during the oxidation of dopamine in the present of cysteine (or other cellular thiols) may contribute to nigral death1. Recent investigations have shown that CysDA possesses strong neurotoxicity and may initiate a sustained increase in intracellular reactive oxygen species (ROS) in neurons leading to DNA oxidation, caspase-3 activation and delayed neuronal death2. In addition, CysDA may undergo further oxidation to yield new species, such as dihydrobenzothiazine, which have been reported to be potent mitochondrial respiratory complex I inhibitors3. Recently there has been intense interest in the effects of dietary antioxidants and polyphenolic compounds, present in fruits and vegetables, to protect against neuronal damage and cognitive decline4. Whilst flavonoids may exert their biological effects via their antioxidant capacity, there is accumulating evidence suggesting that they might exert neuromodulatory activities through the modulation of cellular signalling pathways, in particular the mitogen activated protein kinase (MAPK) pathway5. This study focused on the ability of dietary derived polyphenols to protect against neurotoxicity exerted by endogenously formed CysDA and derived species. In vitro experiments demonstrated that CysDA may be formed during the oxidation of dopamine by tyrosinase or peroxynitrite. However, in presence of polyphenols (resveratrol, hesperetin, caffeic acid and (+)-catechin) a small but significant decrease in CysDA formation was observed. Moreover, these reactions led to the formation of various polyphenol-cysteinyl adducts, which may represent novel metabolic forms present in vivo. Caffeic acid, gallic acid and tyrosol also exerted strong protection against peroxynitrite-induced injury to primary cortical neurons (Figure 1), whilst hesperetin and pelargonidin were observed to protect against CysDA neurotoxicity. The mechanism by which polyphenols inhibited neuronal death was found to be linked to their ability to induce the activation of both Akt/PKB signalling and the ERK1/2 pathways. The protective effects of polyphenols against neurotoxins-induced toxicity will help shed light on their mechanism of neuroprotection

Polyphenols

In recent years there has been intense interest on the potential health effects of dietary polyphenols. Polyphenols are found ubiquitously in plants and are therefore abundant in human diet. Increased polyphenol consumption has been associated with a reduced risk of development of a range of chronic diseases, such as cancer, cardiovascular and neurodegenerative disorders. Initially the antioxidant property of polyphenols was believed to underlie their beneficial effects in vivo. However, they are subject to extensive metabolism in the small intestine, the liver and in the colon following oral ingestion and the resulting circulating metabolites have reduced antioxidant potential. Despite this, other potential mechanisms of action have emerged for polyphenols, which include their interaction with cell signalling pathways and modulation of mitochondrial fuction. In this Chapter we aim to: 1) provide an overview of the different classes of polyphenols, 2) to describe their biosynthesis within plants, 3) to provide an understanding of the metabolism and biotransformation of polyphenols within the body following ingestion and 4) to highlight their potential mechanisms of action in the body, notably their antioxidant and non-antioxidant activities