Epigenetics has provided a new dimension to our understanding of nuclear factor erythroid 2–related factor 2/Kelch-like ECH-associated protein 1 (human NRF2/KEAP1 and murine Nrf2/Keap1) signaling. Unlike the genetic changes affecting DNA sequence, the reversible nature of epigenetic alterations provides an attractive avenue for cancer interception. Thus, targeting epigenetic mechanisms in the corresponding signaling networks represents an enticing strategy for therapeutic intervention with dietary phytochemicals acting at transcriptional, post-transcriptional, and post-translational levels. This regulation involves the interplay of histone modifications and DNA methylation states in the human NFE2L2/KEAP1 and murine Nfe2l2/Keap1 genes, acetylation of lysine residues in NRF2 and Nrf2, interaction with bromodomain and extraterminal domain (BET) acetyl “reader” proteins, and non-coding RNAs such as microRNA (miRNA) and long non-coding RNA (lncRNA). Phytochemicals documented to modulate NRF2 signaling act by reversing hypermethylated states in the CpG islands of NFE2L2 or Nfe2l2, via the inhibition of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), through the induction of ten-eleven translocation (TET) enzymes, or by inducing miRNA to target the 3′-UTR of the corresponding mRNA transcripts. To date, fewer than twenty phytochemicals have been reported as NRF2 epigenetic modifiers, including curcumin, sulforaphane, resveratrol, reserpine, and ursolic acid. This opens avenues for exploring additional dietary phytochemicals that regulate the human epigenome, and the potential for novel strategies to target NRF2 signaling with a view to beneficial interception of cancer and other chronic diseases.

A reliable pipeline to identify DNA methylation signatures in CSF ctDNA could serve as potential biomarkers for MB patients.

Diverse stimuli trigger Nrf2 signaling, which in turn transcriptionally regulates an array of downstream targets, providing for multiple layers of control. While Nrf2 activity largely is governed by posttranslational modification of critical thiol residues in the protein partner and redox sensor Keap1, fine-tuning is provided by additional mechanisms - including epigenetic regulation. Herein, we review the emerging significance of long non-coding RNAs (lncRNA) as downstream targets and upstream regulators of the Nrf2 signaling pathway. Among the ~16000 lncRNAs in GENCODE, some have been validated as transcriptionally regulated by Nrf2 (e.g., LUCAT1, NMRAL2P, ODRUL, ROR and TUG1), and others have been identified as upstream regulators of Nrf2 expression (e.g., HOTAIR, MALAT1, MEG1, NRAL and UCA1). Bioinformatic analyses of annotated human lncRNAs identified putative Nrf2 binding sites in the promoter regions of 13,285 lncRNAs. Further investigation is warranted to validate the many novel lncRNAs as bona fide Nrf2-regulated targets, and their roles in Nrf2 signaling. Nrf2 is considered a promising therapeutic candidate for cancer and other chronic diseases; thus, targeting the associated lncRNAs might provide for a more refined fine-tuning of the system, depending on cellular and pathophysiological context.

Cell Cycle and Apoptosis Regulator 1 (CCAR1) and Cell Cycle and Apoptosis Regulator 2 (CCAR2) have emerged as key players in physiology and pathophysiology, with critical roles in the DNA damage response, nuclear receptor function, and Wnt signaling, among other activities. Contradictory reports exist on the functional duality of CCAR1 and CCAR2 as either tumor promoters or suppressors, suggesting that CCAR1 and CCAR2 have the hallmarks of gene chameleons. We review herein the mechanistic, preclinical, and human translational findings for CCAR1 and CCAR2, based on available RNA and protein expression data from human studies, The Cancer Genome Atlas (TCGA) data mining, gene knockout mouse models, and cell‐based assays. Multiple factors contribute to the divergent activities of CCAR1 and CCAR2, including tissue type, mutation/genetic background, protein‐protein interactions, dynamic regulation via posttranslational modifications, and alternative RNA splicing. An array of protein partners interact with CCAR1 and CCAR2 in the context of tumor promotion and suppression, including β‐catenin, androgen receptor, p21^Cip1/Waf1, tumor protein p53 (p53), sirtuin 1, and histone deacetylase 3. Genetic changes frequently found in cancer, such as TP53 mutation, also serve as critical determinants of survival outcomes in cancer patients. This review seeks to provide the impetus for further investigation into CCAR1 and CCAR2 as potential master regulators of metabolism, aging, and cancer.

Complex interrelationships govern the dynamic interactions between gut microbes, the host, and exogenous drivers of disease outcome. A multi-omics approach to cancer prevention by spinach (SPI) was pursued for the first time in the polyposis in rat colon (Pirc) model. SPI fed for 26 weeks (10% w/w, freeze-dried in the diet) exhibited significant antitumor efficacy and, in the Apc-mutant genetic background, β-catenin remained highly overexpressed in adenomatous polyps. However, in both wild type and Apc-mutant rats, increased gut microbiome diversity after SPI consumption coincided with reversal of taxonomic composition. Metagenomic prediction implicated linoleate and butanoate metabolism, tricarboxylic acid cycle, and pathways in cancer, which was supported by transcriptomic and metabolomic analyses. Thus, tumor suppression by SPI involved marked reshaping of the gut microbiome along with changes in host RNA-miRNA networks. When colon polyps were compared with matched normal-looking tissues via metabolomics, anticancer outcomes were linked to SPI-derived linoleate bioactives with known anti-inflammatory/ proapoptotic mechanisms, as well as N-aceto-2-hydroxybutanoate, consistent with altered butanoate metabolism stemming from increased α-diversity of the gut microbiome. In colon tumors from SPI-fed rats, L-glutamate and N-acetylneuraminate also were reduced, implicating altered mitochondrial energetics and cell surface glycans involved in oncogenic signaling networks and immune evasion. In conclusion, a multi-omics approach to cancer prevention by SPI provided mechanistic support for linoleate and butanoate metabolism, as well as tumor-associated changes in L-glutamate and N-acetylneuraminate. Additional factors, such as the fiber content, also warrant further investigation with a view to delaying colectomy and drug intervention in at-risk patients.

L-Theanine is a unique non-protein amino acid found abundantly in tea leaves. Interest in its potential use as a dietary supplement has surged recently, especially claims related to promoting relaxation and cognitive enhancement. This review surveys the chemistry, metabolism, and purported biological activities of l-theanine. It is well absorbed from the intestine and can cross the blood-brain barrier. Some studies suggest l-theanine may increase alpha waves in the brain associated with relaxation and selective attention, reduce stress and anxiety, and improve sleep quality, though findings are often inconsistent. Potential neuroprotective and anti-seizure effects have also been reported in animal models. When combined with caffeine, l-theanine may improve cognitive performance, alertness and focus. However, the evidence supporting many health claims remains limited, especially the lack of rigorous human clinical trials. While l-theanine exhibits a good safety profile based on toxicology studies, caution is warranted regarding the purported health benefits, until stronger scientific substantiation emerges. Overall, the mechanisms of action and therapeutic potential of l-theanine require further investigation, given the current interest and increasing popularity of this nutraceutical supplement marketed for brain health and relaxation. In the absence of well-designed and carefully controlled human clinical trials, we would urge caution in the use of l-theanine supplements at pharmacologic doses by the wider population, and believe that the science does not yet match the hype behind this trending supplement for brain health and relaxation.