Activation of the Nrf2 Cell Defense Pathway by Ancient Foods: Disease Prevention by Important Molecules and Microbes Lost from the Modern Western Diet

Abstract

The Nrf2 (NFE2L2) cell defense pathway protects against oxidative stress and disorders including cancer and neurodegeneration. Although activated modestly by oxidative stress alone, robust activation of the Nrf2 defense mechanism requires the additional presence of co-factors that facilitate electron exchange. Various molecules exhibit this co-factor function, including sulforaphane from cruciferous vegetables. However, natural co-factors that are potent and widely available from dietary sources have not been identified previously. The objectives of this study were to investigate support of the Nrf2 cell defense pathway by the alkyl catechols: 4-methylcatechol, 4-vinylcatechol, and 4-ethylcatechol. These small electrochemicals are naturally available from numerous sources but have not received attention. Findings reported here illustrate that these compounds are indeed potent co-factors for activation of the Nrf2 pathway both in vitro and in vivo. Each strongly supports expression of Nrf2 target genes in a variety of human cell types; and, in addition, 4-ethylcatechol is orally active in mice. Furthermore, findings reported here identify important and previously unrecognized sources of these compounds, arising from biotransformation of common plant compounds by lactobacilli that express phenolic acid decarboxylase. Thus, for example, Lactobacillus plantarum, Lactobacillus brevis, and Lactobacillus collinoides, which are consumed from a diet rich in traditionally fermented foods and beverages, convert common phenolic acids found in fruits and vegetables to 4-vinylcatechol and/or 4-ethylcatechol. In addition, all of the alkyl catechols are found in wood smoke that was used widely for food preservation. Thus, the potentially numerous sources of alkyl catechols in traditional foods suggest that these co-factors were common in ancient diets. However, with radical changes in food preservation, alkyl catechols have been lost from modern foods. The absence of alkyl catechols from the modern Western diet suggests serious negative consequences for Nrf2 cell defense, resulting in reduced protection against multiple chronic diseases associated with oxidative stress.

Dietary Foeniculum vulgare Mill extract attenuated UVB irradiation-induced skin photoaging by activating of Nrf2 and inhibiting MAPK pathways

“…2, 3 and 4). It should be noted that these polyphenolic compounds are largely broken down by bowel flora and absorbed as smaller phenolic molecules (Senger et al, 2016), which are capable of both directly scavenging free radical and indirectly increasing endogenous cellular antioxidant defenses via activation of the Nrf2 transcriptional pathways, as well as potentially via multiple other mechanisms (Satoh et al, 2014). However, the activation of Nrf2 pathway represents a major mechanism of action for FV, particularly in the skin photoaging.…”

Anti-inflammatory activity of Barleria lupulina: Identification of active compounds that activate the Nrf2 cell defense pathway, organize cortical actin, reduce stress fibers, and improve cell junctions in microvascular endothelial cells

“…In contrast, HAE-BL had no significant effects on transcripts encoding two endothelial cell structural “housekeeping” genes, CD31 (PECAM-1) and VE-cadherin (Figure 1A). HO-1, NQO1, and G6PD are each well-established target genes of the Nrf2 transcription factor (Cho et al, 2002; Holmstrom et al, 2013; Li et al, 2004; Mitsuishi et al, 2012), whereas CD31 and VE-cadherin are not regulated by Nrf2 (Senger et al, 2016). Thus, HAE-BL selectively activates Nrf2-mediated transcription.…”

“…For all other primer sequences see ref. (Senger et al, 2016). All PCR reactions were performed in duplicate and copy numbers were calculated from standard curves generated from a master template (Shih and Smith, 2005).…”

“…The Nrf2 transcription factor, through binding to antioxidant response elements in ~ 200 genes, induces expression of anti-oxidant and detoxifying enzymes that protect against oxidative damage and also provide protection against toxic foreign chemical substances through phase II enzyme modification (Dinkova-Kostova and Abramov, 2015; Holmstrom et al, 2013). Compelling evidence for the importance of the Nrf2 pathway for disease prevention and control of tissue damage associated with inflammation comes from numerous studies with mice lacking the Nrf2 gene (reviewed in (Senger et al, 2016)). Also, consistent with folklore use of BL for diabetic complications, Nrf2 has been implicated in protection from diabetic pathology (de Haan, 2011; Evans and Goldfine, 2016; Li et al, 2012; Long et al, 2016).…”

Possible Role of Nrf2 in Oxidative and Inflammatory Processes During Menopause

“…Among these compounds are curcumin, sulforaphane, anthocyanins and alkyl catechol. Lactobacilli are important too, as they contain phenolic acid decarboxylase enzyme, alkyl catechol (Figure 2) [73][74][75]. …”