Hormetic Dietary Phytochemicals

Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Neuromolecular medicine (Impact Factor: 3.68). 07/2008; 10(4):236-46. DOI: 10.1007/s12017-008-8037-y
Source: PubMed


Compelling evidence from epidemiological studies suggests beneficial roles of dietary phytochemicals in protecting against chronic disorders such as cancer, and inflammatory and cardiovascular diseases. Emerging findings suggest that several dietary phytochemicals also benefit the nervous system and, when consumed regularly, may reduce the risk of disorders such as Alzheimer's and Parkinson's diseases. The evidence supporting health benefits of vegetables and fruits provide a rationale for identification of the specific phytochemicals responsible, and for investigation of their molecular and cellular mechanisms of action. One general mechanism of action of phytochemicals that is emerging from recent studies is that they activate adaptive cellular stress response pathways. From an evolutionary perspective, the noxious properties of such phytochemicals play an important role in dissuading insects and other pests from eating the plants. However at the subtoxic doses ingested by humans that consume the plants, the phytochemicals induce mild cellular stress responses. This phenomenon has been widely observed in biology and medicine, and has been described as 'preconditioning' or 'hormesis.' Hormetic pathways activated by phytochemicals may involve kinases and transcription factors that induce the expression of genes that encode antioxidant enzymes, protein chaperones, phase-2 enzymes, neurotrophic factors, and other cytoprotective proteins. Specific examples of such pathways include the sirtuin-FOXO pathway, the NF-kappaB pathway, and the Nrf-2/ARE pathway. In this article, we describe the hormesis hypothesis of phytochemical actions with a focus on the Nrf2/ARE signaling pathway as a prototypical example of a neuroprotective mechanism of action of specific dietary phytochemicals.

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    • "Activation of such hormetic neuronal pathways results in production of cytoprotective proteins, including neurotrophic factors, protein chaperones, phase II enzymes, and antiapoptotic proteins (Son et al., 2008). In this context , the flavonoid resveratrol activates multiple hormetic pathways, including stress-resistance pathways involving sirtunins, protecting neurons against ischemic injury (Kaplan et al., 2005; Parker et al., 2005). "
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    ABSTRACT: Dietary phytochemicals, in particular flavonoids, have been suggested to limit neurodegeneration in a variety of neurological diseases and ameliorate age-related cognitive impairments. Emerging evidence suggests that absorbed dietary flavonoids and their metabolites traverse across the blood–brain barrier and exert multiple neuropharmacological actions. Flavonoids are demonstrated to influence critical signaling molecules, gene expression, and protein (kinases and enzymes) function and thereby remodulate the innate architecture of the brain to influence cognitive function and exert a neuroprotective effect. The underlying mechanism is comprised of the regulation of neuronal signaling cascades and transcription factors, which are crucial in inducing synaptic plasticity, suppression of neuroinflammatory processes, promotion of cerebrovascular perfusion, and activation of adaptive cellular stress response pathways (involving the hormetic effect) that encode expression of genes to protect against oxidative stressors. This review provides insight into the potential evidence for the association between a flavonoid-rich diet and cognitive enhancement with age-related neurodegenerative diseases.
    Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain Disease: Prevention and Therapy, 1st Edition edited by Ronald R. Watson and Victor R. Preedy, 01/2015: chapter Dietary Supplements as Cognitive Enhancers The Role of Flavonoid-Rich Foods and their Relevance in Age-Related Neurodegeneration: pages 281−290; Academic Press, Elsevier., ISBN: 978-0-12-411462-3
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    • "nefits assume unimpaired activation of stress response pathways and downstream antioxidant defense systems . Interest - ingly , activation of the phytochemical - sensitive nuclear factor erythroid - 2 p45 - related factor 2 and / or antioxidant response element stress response pathway has been shown to involve several insulin signaling molecules ( Son et al . , 2008 ; Wang et al . , 2012 ; Wu et al . , 2006 ; Yu et al . , 1999 ) that have been shown to be downregulated in human AD and AD animal models including in this study ( Bomfim et al . , 2012 ; Chua et al . , 2012 ; Ma et al . , 2009 ; Maesako et al . , 2012 ; Rivera et al . , 2005 ; Talbot et al . , 2012 ) . Furthermore , damage to small mol"
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    ABSTRACT: Food combinations have been associated with lower incidence of Alzheimer’s disease (AD). We hypothesized that a combination whole-food diet (WFD) containing freeze-dried fish, vegetables and fruits would improve cognitive function in TgCRND8 mice by modulating brain insulin-signaling and neuroinflammation. Cognitive function was assessed by a comprehensive battery of tasks adapted to the Morris water maze. Unexpectedly, a ‘Diet x Transgene’ interaction was observed in which transgenic animals fed the WFD exhibited even worse cognitive function than their transgenic counterparts fed the control diet on tests of spatial memory (P<0.01) and strategic rule learning (P=0.034). These behavioural deficits coincided with higher hippocampal gene expression of tumor necrosis factor-α (P=0.013). There were no differences in cortical amyloid-β peptide species according to diet. These results indicate that a dietary profile identified from epidemiological studies exacerbated cognitive dysfunction and neuroinflammation in a mouse model of familial AD. We suggest that normally adaptive cellular responses to dietary phytochemicals were impaired by amyloid-beta deposition leading to increased oxidative stress, neuroinflammation, and behavioural deficits.
    Neurobiology of Aging 08/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.08.013 · 5.01 Impact Factor
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    • "For example, dietary restriction increases levels of brain derived neurotrophic factor, neurogenesis, and heat shock proteins (Mattson et al. 2004). Mattson has further proposed that dietary phytochemicals ingested from plants can precondition against multiple diseases , including Parkinson's and Alzheimer's disease (Son et al. 2008). From an evolutionary point of view, phytochemicals may activate stressresponsive pathways because they are designed to repel insects, molds, and even mammals. "
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    ABSTRACT: Although severe stress can elicit toxicity, mild stress often elicits adaptations. Here we review the literature on stress-induced adaptations versus stress sensitization in models of neurodegenerative diseases. We also describe our recent findings that chronic proteotoxic stress can elicit adaptations if the dose is low but that high-dose proteotoxic stress sensitizes cells to subsequent challenges. In these experiments, long-term, low-dose proteasome inhibition elicited protection in a superoxide dismutase-dependent manner. In contrast, acute, high-dose proteotoxic stress sensitized cells to subsequent proteotoxic challenges by eliciting catastrophic loss of glutathione. However, even in the latter model of synergistic toxicity, several defensive proteins were upregulated by severe proteotoxicity. This led us to wonder whether high-dose proteotoxic stress can elicit protection against subsequent challenges in astrocytes, a cell type well known for their resilience. In support of this new hypothesis, we found that the astrocytes that survived severe proteotoxicity became harder to kill. The adaptive mechanism was glutathione dependent. If these findings can be generalized to the human brain, similar endogenous adaptations may help explain why neurodegenerative diseases are so delayed in appearance and so slow to progress. In contrast, sensitization to severe stress may explain why defenses eventually collapse in vulnerable neurons.
    Dose-Response 03/2014; 12(1):24-56. DOI:10.2203/dose-response.13-016.Leak · 1.22 Impact Factor
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