Hormetic Dietary Phytochemicals

Abstract

Compelling evidence from epidemiological studies suggest 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 relatively small doses ingested by humans that consume the plants, the phytochemicals are not toxic and instead 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-κB 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.

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

“…In contrast, when ingested by humans and other mammals at the relatively low amounts contained in the dietary fruits and vegetables, they can protect against a variety of adverse disorders by activating the adaptive stress response pathways. In this context several studies have demonstrated the hormetic mechanisms of action of resveratrol, curcumin, sulforaphanes and catechins in cultured cells and in experimental animal [39,40]. Hormesis pathways activated by phytochemicals include Nrf-2 which stimulates transcription of genes controlled by the antioxidant response element, histone deacetylases of the sirtuin family, and FOXO transcription factors [40].…”

“…In this context several studies have demonstrated the hormetic mechanisms of action of resveratrol, curcumin, sulforaphanes and catechins in cultured cells and in experimental animal [39,40]. Hormesis pathways activated by phytochemicals include Nrf-2 which stimulates transcription of genes controlled by the antioxidant response element, histone deacetylases of the sirtuin family, and FOXO transcription factors [40]. Activation of these pathways confers protection by up-regulating expression of antioxidant enzymes, detoxifying compounds, protein chaperones, and trophic factors.…”

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

“…Curcumin, a yellow compound bioactive in turmeric, and its derivatives were found to possess antioxidative and anti-inflammatory properties that could cure cerebral oedema and is mainly helpful in cases of kidney pathologies through activation of the Nrf2-ARE pathway (Yang et al 2009;Son et al 2008). Caffeic acid, a phenolic acid, consists of both nucleophilic and an electrophilic moiety in its structure.…”

Adaptation and Sensitization to Proteotoxic Stress

“…Only a small number of studies have considered the possibility of preconditioning in models of neurodegenerative diseases and some of these will be described here. First, Mark Mattson has proposed that dietary and behavioral manipulations such as exercise and food restriction may protect against models of neurodegeneration by activating stress-responsive pathways (Duan and Mattson 1999;Guo et al 2000;Mattson et al 2004;Son et al 2008). For example, dietary restriction increases levels of brain derived neurotrophic factor, neurogenesis, and heat shock proteins (Mattson et al 2004).…”