Two 2020 reviews covered some aspects of a broccoli sprouts primary action – NRF2 signaling pathway activation:
“Full understanding of the properties of drug candidates rely partly on the identification, validation, and use of biomarkers to optimize clinical applications. This review focuses on results from clinical trials with four agents known to target NRF2 signaling in preclinical studies, and evaluates the successes and limitations of biomarkers focused on:
- Expression of NRF2 target genes [AKR1, GCL, GST, HMOX1, NQO1] and others [HDAC, HSP];
- Inflammation [COX-2, CRP, IL-1β, IL-6, IP-10, MCP-1, MIG, NF-κB, TNF-α] and oxidative stress [8-OHdG, Cys/CySS, GSH/GSSG] biomarkers;
- Carcinogen metabolism and adduct biomarkers in unavoidably exposed populations; and
- Targeted and untargeted metabolomics [HDL, LDL, TG].
No biomarkers excel at defining pharmacodynamic actions in this setting.
SFN [sulforaphane] seems to affect multiple downstream pathways associated with anti-inflammatory actions. NRF2 signaling may be but one pivotal pathway.
SFN is generally considered to be the most potent natural product inducer of Nrf2 signaling. Studies in which these actions are diminished or abrogated in parallel experiments in Nrf2-disrupted mice provide the strongest lines of evidence for a key role of this transcription factor in its actions.
It is equally evident that other modes of action contribute to the molecular responses to SFN in animals and humans. Such polypharmacy may well contribute to the efficacy of the agent in disease prevention and mitigation, but obfuscates the value of specific pharmacodynamic biomarkers in the clinical development and evaluation of SFN.”
https://www.mdpi.com/2076-3921/9/8/716/htm “Current Landscape of NRF2 Biomarkers in Clinical Trials”
Why do researchers still not use epigenetic clocks in sulforaphane clinical trials? Forty mentions of disease in this review, but no consideration of aging?
This was another example of how researchers – even when stuck in a paradigm they know doesn’t sufficiently explain their area (“No biomarkers excel”) – don’t investigate other associated research areas. Why not?
Here’s what Part 2 of Rejuvenation therapy and sulforaphane had to say to those stuck on biomarkers:
“While clinical biomarkers have obvious advantages (being indicative of organ dysfunction or disease), they are neither sufficiently mechanistic nor proximal to fundamental mechanisms of aging to serve as indicators of them. It has long been recognized that epigenetic changes are one of several primary hallmarks of aging.
DNA methylation epigenetic clocks capture aspects of biological age.”
The second review Epigenetic Regulation of NRF2/KEAP1 by Phytochemicals also completely whiffed on epigenetic clocks. One mention of aging in this review, but it wasn’t of:
- Citation 104 from Archives of Gerontology and Geriatrics; nor of
- Citation 108 from the March 31, 2020, Aging journal; nor of
- Citation 131 “Dietary epigenetics in cancer and aging.”
But epigenetic clock and aging associations were certainly in this review’s scope. For example, Citation 119 said:
“Nrf2 transcriptional activity declines with age, leading to age-related GSH loss among other losses associated with Nrf2-activated genes. This effect has implications, too, for decline in vascular function with age. Some of the age-related decline in function can be restored with Nrf2 activation by SFN.”
Why would people bother with phytochemicals (buzzword “compounds produced by plants”) unless they needed to either ameliorate symptoms or address causes?
“Epigenetic Regulation of NRF2/KEAP1 by Phytochemicals” doesn’t occur in just laboratory situations. It’s also part of daily life.
These reviewers were straight-forward with side effects for two of the first review’s four items:
“The best known NRF2 activator that has obtained clinical approval is dimethyl fumarate for the treatment of multiple sclerosis. However, it has several side effects, including allergic reactions and gastrointestinal disturbance. There are a few related agents in clinical trials, such as Bardoxolone and SFX-01, a synthetic derivative of sulforaphane, which also exhibit less than desirable outcomes.”