Beyond antioxidants: the cellular and molecular interactions of flavonoids and how these underpin their actions on the brain

Spencer, Jeremy P. E.

doi:10.1017/s0029665110000054

Cited by 143 publications

(95 citation statements)

References 211 publications

(352 reference statements)

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“…(43) Although we used a FFQ to estimate dietary intakes this is based on the validated European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk questionnaire, (28,29) which accurately reflects habitual intake (44) and was able to distinguish between the main classes of foods contributing to total flavonoids and the subclasses in this cohort. Although there has been significant interest in the relationship between flavonoids and cardiovascular health and cognitive function, (32,45) to date we are aware of only one other population study investigating the association between flavonoid intake and bone health. (4) Our study was able to examine the association with a more comprehensive estimation of flavonoid intake and the range of subclasses than has been used previously.…”

Section: Discussionmentioning

confidence: 99%

Habitual flavonoid intakes are positively associated with bone mineral density in women

Welch

Macgregor

Jennings

et al. 2012

Journal of Bone and Mineral Research

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Dietary flavonoids exert bone-protective effects in animal models, but there is limited information on the effect of different flavonoid subclasses on bone health in humans. The aim of this observational study was to examine the association between habitual intake of flavonoid subclasses with bone mineral density (BMD) in a cohort of female twins. A total of 3160 women from the TwinsUK adult twin registry participated in the study. Habitual intakes of flavonoids and subclasses (flavanones, anthocyanins, flavan-3-ols, polymers, flavonols, and flavones) were calculated from semiquantitative food frequency questionnaires using an updated and extended U.S. Department of Agriculture (USDA) database. Bone density was measured using dual-energy X-ray absorptiometry. In multivariate analyses, total flavonoid intake was positively associated with higher BMD at the spine but not at the hip. For the subclasses, the magnitude of effect was greatest for anthocyanins, with a 0.034 g/cm 2 (3.4%) and 0.029 g/cm 2 (3.1%) higher BMD at the spine and hip, respectively, for women in the highest intake quintile compared to those in the lowest. Participants in the top quintile of flavone intake had a higher BMD at both sites; 0.021 g/cm 2 (spine) and 0.026 g/cm 2 (hip). At the spine, a greater intake of flavonols and polymers was associated with a higher BMD (0.021 and 0.024 g/cm 2 , respectively), whereas a higher flavanone intake was positively associated with hip BMD (0.008 g/cm 2 ). In conclusion, total flavonoid intake was positively associated with BMD, with effects observed for anthocyanins and flavones at both the hip and spine, supporting a role for flavonoids present in plant-based foods on bone health. ß

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Section: Discussionmentioning

confidence: 99%

Habitual flavonoid intakes are positively associated with bone mineral density in women

Welch

Macgregor

Jennings

et al. 2012

Journal of Bone and Mineral Research

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“…The consumption of flavonoid-rich foods and beverages has been suggested to limit the neurodegeneration associated with a variety of neurological disorders and to prevent or reverse deteriorations in brain (Spencer, 2010). Originally, it was thought that such actions were mediated by the antioxidant capacity of flavonoids (Spencer, 2010).…”

Section: Discussionmentioning

confidence: 99%

Kaempferol Attenuates 4-Hydroxynonenal-Induced Apoptosis in PC12 Cells by Directly Inhibiting NADPH Oxidase

Jang

Kim

Shim

et al. 2011

J Pharmacol Exp Ther

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Kaempferol, a natural flavonoid isolated from various plant sources, has been identified as a potential neuroprotectant. In this study, we investigated the protective effect of kaempferol against 4-hydroxynonenal (HNE)-induced apoptosis in PC12 rat pheochromocytoma cells. Kaempferol inhibited 4-HNE-mediated apoptosis, characterized by nuclear condensation, down-regulation of antiapoptotic protein Bcl-2, and activation of proapoptotic caspase-3. Kaempferol inhibited 4-HNE-induced phosphorylation of c-Jun N-terminal protein kinase (JNK). More importantly, kaempferol directly bound p47 phox , a cytosolic subunit of NADPH oxidase (NOX), and significantly inhibited 4-HNE-induced activation of NOX. The antiapoptotic effects of kaempferol were replicated by the NOX inhibitor apocynin, suggesting that NOX is an important enzyme in its effects. Our results suggest that kaempferol attenuates 4-HNEinduced activation of JNK and apoptosis by binding p47 phox of NOX and potently inhibiting activation of the NOX-JNK signaling pathway in neuron-like cells. Altogether, these results suggest that kaempferol may be a potent prophylactic against NOX-mediated neurodegeneration.

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“…58 Nevertheless, due to their limited absorption and their low bioavailability in the brain, increasing evidence demonstrates that they are able to interact with the cellular and molecular components of the brain responsible for memory, having the potential to protect vulnerable neurons, enhance existing neuronal function, stimulate neuronal regeneration, and induce neurogenesis. 58,59 ■ EFFECT OF FLAVONOIDS ON APP PROCESSING Several flavonoids have been shown to inhibit the development of AD and to reverse cognitive deficits in rodent models, indicating their potential therapeutic utility. Since altered APP processing leading to increased Aβ production is a key pathogenic feature of AD, several studies have been directed toward the antiamyloidogenic properties of flavonoids.…”

Section: ■ Flavonoidsmentioning

confidence: 99%

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Baptista

Henriques

Silva

et al. 2014

ACS Chem. Neurosci.

166

111

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Alzheimer's disease is characterized by pathological aggregation of protein tau and amyloid-β peptides, both of which are considered to be toxic to neurons. Naturally occurring dietary flavonoids have received considerable attention as alternative candidates for Alzheimer's therapy taking into account their antiamyloidogenic, antioxidative, and anti-inflammatory properties. Experimental evidence supports the hypothesis that certain flavonoids may protect against Alzheimer's disease in part by interfering with the generation and assembly of amyloid-β peptides into neurotoxic oligomeric aggregates and also by reducing tau aggregation. Several mechanisms have been proposed for the ability of flavonoids to prevent the onset or to slow the progression of the disease. Some mechanisms include their interaction with important signaling pathways in the brain like the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways that regulate prosurvival transcription factors and gene expression. Other processes include the disruption of amyloid-β aggregation and alterations in amyloid precursor protein processing through the inhibition of β-secretase and/or activation of α-secretase, and inhibiting cyclin-dependent kinase-5 and glycogen synthase kinase-3β activation, preventing abnormal tau phosphorylation. The interaction of flavonoids with different signaling pathways put forward their therapeutic potential to prevent the onset and progression of Alzheimer's disease and to promote cognitive performance. Nevertheless, further studies are needed to give additional insight into the specific mechanisms by which flavonoids exert their potential neuroprotective actions in the brain of Alzheimer's disease patients. KEYWORDS: Flavonoids, Alzheimer's disease, amyloid precursor protein, amyloid beta, BACE-1, tau, signaling A lzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia worldwide. The major histopathological hallmarks of AD include proteinous aggregates in the form of neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau 1,2 and extracellular senile plaques, which are deposits of heterogeneously sized small peptides of amyloid-β (Aβ) that are formed via sequential proteolytic cleavages of the amyloid precursor protein (APP) 3 (Figure 1). Dominant mutations in APP, presenilin-1 (PS1) or PS2 are responsible for the early onset or familial form of AD. These mutations have been shown to profoundly alter APP metabolism, favoring the production of aggregation-prone Aβ species, these findings formed the basis for the "amyloid cascade hypothesis" of AD pathogenesis. This broadly accepted hypothesis states that the generation of neurotoxic Aβ peptides by β-secretase and γ-secretase are at the basis of AD pathophysiology. Other hallmarks of this disease, like neurotransmitter changes 4,5 and neuronal and synapse loss in the neocortex and the hippocampus 6,7 develop as a consequence of this event.■ AMYLOID PRECURSOR PROTEIN APP belongs to a protein f...

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Beyond antioxidants: the cellular and molecular interactions of flavonoids and how these underpin their actions on the brain

Cited by 143 publications

References 211 publications

Habitual flavonoid intakes are positively associated with bone mineral density in women

Habitual flavonoid intakes are positively associated with bone mineral density in women

Kaempferol Attenuates 4-Hydroxynonenal-Induced Apoptosis in PC12 Cells by Directly Inhibiting NADPH Oxidase

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

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