FMF Science Digest Dec20

Hello, Premium Members!

We have a special treat for you this week: Our entire issue of the Science Digest is devoted to the fascinating science surrounding sulforaphane.

Sulforaphane is a bioactive compound derived from certain cruciferous vegetables, including broccoli (especially broccoli sprouts) and red kale.

Robust evidence from epidemiological, clinical, rodent, and in vitro studies indicates that sulforaphane exhibits antioxidant and anti-inflammatory properties and may be beneficial against a wide range of diseases, including autism, cardiovascular disease, neurological disease, cancer, and many others.

Sulforaphane exerts its preventive and therapeutic effects through a variety of mechanisms, such as inhibition of phase I drug-metabolizing enzymes, induction of phase 2 protective enzymes, and inhibition of cell proliferation, among others.

Perhaps the most studied mechanism by which sulforaphane works is its activation of Nrf2, a cellular protein that regulates the expression of antioxidant and stress response proteins that provide protection against oxidative stress due to injury and inflammation. Sulforaphane is the most potent naturally occurring inducer of Nrf2.

Read on to learn more about how sulforaphane treatment…

Increases glutathione levels in the brain
Improves blood glucose control in obese people with type 2 diabetes.
Promotes urinary excretion of benzene, a common air pollutant.

And much more!

In fact, there were so many studies we wanted to share with you that we ran out of room! Look for a comprehensive overview article about sulforaphane, coming soon to the FMF website.

But that’s not all!

Expect to find find our Q&A with sulforaphane expert Dr. Jed Faheyon your members-only podcast feed (which you can find on the member’s dashboard) soon. This was a great Q&A that covered a broad range of sulforaphane-related topics and much more.

ICYMI: Learn about sprouting broccoli and the science of sulforaphane in our brand-new 15-page sprouting guide! Read the guide to learn…

How to safely sprout broccoli at home
The history of chemoprotection (from Dr. Fahey)
Practical tips to achieve samurai-level finesse when it comes to sprouting

And coming soon: a companion video for quick tips on how to become an expert at sprouting!

Enjoy reading, watching, and sprouting!

Rhonda and team
Science News Digest – November 15, 2020
A pilot trial finds sulforaphane treatment increases glutathione levels in the brain.

Cellular damage incurred by oxidative stress underlies the pathophysiology of many chronic health disorders, including neuropsychiatric conditions such as schizophrenia. Glutathione, an antioxidant compound produced by the body’s cells, helps prevent damage from oxidative stress. Evidence from a 2018 study suggests that sulforaphane increases glutathione in the brain.

Scientists typically rely on magnetic resonance spectrometry (MRS) for measuring glutathione levels in brain tissue. Evidence suggests MRS is inadequate, however, and often yields inconsistent results across studies. These inconsistencies have prompted some investigators to explore the reliability of glutathione level measurements in blood as an indicator of oxidative stress-associated brain changes.

The pilot clinical study involved nine healthy adults. Eight of the participants were between 21 and 26 years old; one was 56 years old. Each of the participants took 100 micromoles of sulforaphane (from a standardized broccoli sprout extract) by mouth every morning for one week. The authors of the study collected urine and blood specimens from the participants and performed MRS scans on their brains prior to the first dose of sulforaphane and within four hours of the final dose.

At the end of the week-long study, the participants’ blood cell glutathione levels increased 32 percent. The MRS scans revealed similar increases in the thalamus, a region of the brain involved in information processing and a key player in schizophrenia. These observations were consistent regardless of age, sex, or race of the participants.

These findings suggest that sulforaphane shows promise as a therapeutic strategy for modulating oxidative stress in the brain, an underlying feature of schizophrenia. Some evidence indicates that moringin, an isothiocyanate compound derived from moringa, may be useful in treating some of the symptoms of schizophrenia. Watch this clip in which Dr. Jed Fahey describes the health benefits associated with moringin and discusses the chemical structure differences between it and sulforaphane.

Link to full study.

Sulforaphane improves blood glucose control in obese people with type 2 diabetes.

Type 2 diabetes is a progressive metabolic disorder characterized by high blood glucose levels and insulin resistance. Long-term complications from poorly controlled type 2 diabetes include heart disease, stroke, and kidney failure, among others. Findings from a 2017 study demonstrated that sulforaphane reduces glucose production in the liver and improves blood glucose control.

Glucose is the body’s primary metabolic fuel. In the fasted state, the body can produce glucose via gluconeogenesis, a highly conserved pathway that occurs primarily in the liver. Increased liver gluconeogenesis among people with type 2 diabetes is a major contributor to high blood glucose and subsequent disease complications.

The authors of the study investigated the effects of sulforaphane in several rodent models of type 2 diabetes and found that sulforaphane ameliorated many of the hallmark characteristics of the disease. Then they assessed sulforaphane’s effects in 97 people with type 2 diabetes. Sixty of the participants had well-regulated disease, but 37 had poorly regulated disease. Of those with poorly regulated disease, 17 had obesity. Nearly all of the participants took metformin, a common blood glucose-lowering drug.

Participants received either an oral placebo or a glucoraphanin-rich broccoli sprout extract every day for 12 weeks. The authors of the study measured the participants’ fasting blood glucose and HbA1c (a measure of long-term blood glucose control) levels and assessed their glucose tolerance prior to and after the intervention.

Sulforaphane administration improved fasting blood glucose and HbA1c levels in the obese participants who had poorly regulated type 2 diabetes. Sulforaphane mediated these effects via Nrf2 activity and subsequent reduced expression of enzymes that promote glucose production in the liver.

These findings suggest that sulforaphane ameliorates some of the hallmark characteristics of diabetes in humans. The mechanisms by which sulforaphane mediates these effects differ from those of metformin, suggesting that the two could work in a complementary manner to improve blood glucose control in obese people with type 2 diabetes.

Link to full study.
Learn more about metformin in our overview article.

Sulforaphane promotes urinary excretion of benzene, a common air pollutant.

Sulforaphane promotes the production of glutathione, a powerful antioxidant that facilitates the body’s excretion of toxic substances. When glutathione binds with benzene, a known carcinogen present in air pollution, the two form mercapturic acids, which can be excreted and measured in urine. Findings from a 2019 study demonstrated that sulforaphane provided in a broccoli sprout beverage promoted excretion of benzene, as reflected in urinary mercapturic acid levels.

The intervention study involved 170 healthy adult participants between the ages of 21 and 65 years living in Qidong, China, an area known for its high levels of air pollution. The participants drank a placebo or a broccoli-sprout beverage containing one of three doses of sulforaphane – “high,” “medium,” or “low” – twice a day for a period of 10 days. After drinking the beverage, the participants provided a urine sample, which was assessed for benzene metabolites.

The authors of the study found that the high dose of sulforaphane markedly increased the production of several urinary metabolites. In particular, excretion of mercapturic acids increased by more than 63 percent in those taking the high dose. Mercapturic acid excretion in those who received the medium and low dose was not significantly different from those who took the placebo.

These findings demonstrated that a broccoli sprout beverage containing sulforaphane enhanced the detoxication of benzene, an important airborne pollutant, and suggest that population-based strategies that employ a dietary approach are viable options for improving healthspan in humans.

Link to full study.
Watch this clip in which Dr. Jed Fahey describes sulforaphane’s chemoprotective qualities against benzene exposure.

Sulforaphane reduces behavioral symptoms of autism in young men.

Autism spectrum disorder, or ASD, is a neurodevelopmental disorder characterized by impaired social interaction and communication, as well as restrictive, repetitive patterns of behavior. ASD affects roughly one in 68 people and is more common among males than females. A 2014 study showed that sulforaphane reduces communication impairments and behavioral symptoms in young men with autism.

Sulforaphane demonstrates low toxicity. Previous research has demonstrated that sulforaphane reverses physiological anomalies commonly associated with ASD, including increased oxidative stress, mitochondrial dysfunction, and neuroinflammation.

The placebo-controlled, double-blind, randomized trial involved 44 young men between the ages of 13 and 27 years who had been diagnosed with moderate to severe ASD. The authors of the study gave 29 of the participants sulforaphane derived from broccoli sprout extracts and gave the remaining participants a placebo. Participants received their respective treatments for 18 weeks, followed by four weeks without treatment.

Sulforaphane doses ranged between 50 and 150 micromoles (~9 milligrams and 26 milligrams, respectively). The participants’ parents, caregivers, and physicians provided assessments of the young men’s behavior using the Aberrant Behavior Checklist, Social Responsiveness Scale, and Clinical Global Impression Improvement Scale (CGI-I).

After 18 weeks on the treatment, the participants who took the placebo experienced little change, but those who took the sulforaphane showed marked improvements in their behaviors. In particular, the CGI-I scores reflected improvements in social interaction, behavior, and verbal communication. After the sulforaphane treatment ended, the participants’ scores rose toward pretreatment levels on all assessments.

These findings suggest that sulforaphane ameliorates many of the behavioral symptoms associated with ASD. A follow-up study reflected similar effects.

Link to full study.

Sulforaphane reduces biochemical recurrence in men who have had prostate cancer.

Prostate cancer is the second most common cancer among men, affecting more than 1.3 million men worldwide. Many men undergo radical prostatectomy to treat their cancer. Findings from a 2015 study demonstrated that sulforaphane reduces biochemical recurrence in men who have had prostate cancer.

Biochemical recurrence is a phenomenon in which serum levels of prostate specific antigen (PSA) levels increase. It is an indicator of localized or metastatic disease. As many as 40 percent of men treated with radical prostatectomy experience biochemical recurrence; more than one-third of these will develop metastatic disease.

The double-blind, randomized, placebo-controlled study involved 75 men (average age, 69 years) who had undergone radical prostatectomy and were experiencing increased PSA levels. Roughly half of the men took a supplement providing 60 milligrams of sulforaphane for six months; the other half took a placebo. The authors of the study measured the men’s PSA levels before and two months after the treatment ended.

Increases in the average PSA levels were much lower among the men who took the sulforaphane. The PSA doubling time among men who took sulforaphane was ~29 months; doubling time among the men who took the placebo was ~16 months – an 86 percent difference. The effects of sulforaphane remained up to three months after the intervention.

These findings suggest that sulforaphane shows promise as a strategy to prevent biochemical recurrence among men who have had radical prostatectomy for prostate cancer. Additional studies are needed to confirm these findings.

Link to full study.

Sulforaphane protects the brain during stroke via hormetic preconditioning.

Stroke is one of the leading causes of death and disability worldwide, claiming the lives of roughly 5 million people and leaving another 5 million permanently disabled every year. A 2013 study demonstrated that sulforaphane protects the brain during ischemic stroke via hormetic preconditioning.

Ischemic stroke occurs when blood flow to the brain is reduced or interrupted, starving neurons of oxygen and nutrients. Neuronal death occurs in the immediate area of a stroke within the first few hours of the incident, but nearby cells can be rescued with appropriate therapies. Heme oxygenase-1 (HO-1), an antioxidant enzyme, attenuates neuronal injury after a stroke. Nrf2, a protein that regulates the expression of antioxidant and stress response proteins, induces HO-1 expression.

The authors of the study gave mice sulforaphane (5 milligrams per kilogram of body weight) or corn oil with saline via injection. After the mice experienced a stroke, the authors measured the animals’ Nrf2 and HO-1 gene expression and assessed behavioral changes, blood-brain barrier integrity, and neurological deficits.

The mice that received sulforaphane treatment showed increased HO-1 expression, reduced blood-brain barrier damage, and fewer neurological deficits than mice that received the corn oil/saline. Levels of peroxynitrite, a short-lived reactive oxygen species associated with cell death, increased in the mice, suggesting that hormetic preconditioning mediated the protection sulforaphane provided against stroke.

These findings suggest that dietary or supplemental interventions (such as sulforaphane) that precondition the brain against injury offer promise as strategies to reduce complications associated with stroke.

Link to study abstract.

Gut microbial conversion of glucosinolates to isothiocyanates is highly variable in humans.

Glucoraphanin, a precursor to sulforaphane, is a type of glucosinolate found primarily in broccoli and kale. Its conversion to sulforaphane requires myrosinase, an enzyme co-located within the leaves, stems, and other components of the plants in which it is found. Cooking temperatures inactivate myrosinase, effectively preventing isothiocyanate conversion and allowing unhydrolyzed glucosinolates to pass into the gut. In humans, myrosinase-producing gut bacteria can convert these glucosinolates to their cognate isothiocyanates. Findings from a 2012 study indicate that microbial conversion of glucosinolates to isothiocyanates is highly variable.

Previous research has demonstrated that sulforaphane undergoes extensive metabolism in humans, ultimately producing a class of compounds called dithiocarbamates. These compouds are excreted in the urine and account for as much as 90 percent of the administered sulforaphane over a 24-hour period. Dithiocarbamate levels in urine serve as a biomarker of glucosinolate intake.

The study involved two dissimilar groups of people: rural Han Chinese and Baltimoreans of various races. The participants abstained from cruciferous vegetable consumption for three days prior to the beginning of the study. They had not taken antibiotics for two weeks prior. Each of the participants kept a food diary, provided their medical history, and kept track of their bowel activity. The participants took a glucoraphanin-rich broccoli sprout extract that provided 200 micromoles of glucoraphanin in water. The authors of the study collected urine samples from 8 a.m. to 4 p.m. and from 4 p.m. until 8 a.m. on the following morning.

They found that microbial-induced conversion of glucoraphanin to sulforaphane is highly variable (ranging from 1 to 40 percent of dose) and subject to interindividual differences in gut bacteria populations. As such, conversion is distinguished by “high converters” – people with high elimination profiles, and “low converters”– those with low elimination profiles. The authors of the study identified no demographic factors that affected conversion efficiency, but they did note that conversion of glucoraphanin to dithiocarbamate was greater during the day.

Link to full study.
Watch this clip in which Dr. Jed Fahey describes some of the factors that influence the conversion of myrosinase-driven conversion of glucoraphanin to sulforaphane.

Determining the optimal dose and source of sulforaphane poses challenges.

A substantial body of evidence from experimental, epidemiological, and clinical studies demonstrates the beneficial effects of sulforaphane consumption on human health. Many questions remain, however, regarding optimal formulation, bioavailability, and dosage of sulforaphane. A 2019 review discusses these and other aspects of the current state of evidence surrounding sulforaphane.

Sulforaphane is the end-product of a chemical reaction between two naturally occurring plant compounds – glucoraphanin and myrosinase. These compounds, often referred to as secondary metabolites, are not required for the plant’s growth or reproduction. Rather, they confer an advantage to the plant, particularly in terms of defense. Glucoraphanin content in broccoli sprouts and mature broccoli vary across species and cultivar and is influenced by factors such as soil and growing conditions, harvest time, and post-harvest storage.

Most rodent studies of sulforaphane’s effects administer the end product via oral, intraperitoneal, or topical means. The median effective dose is 175 micromoles (~30 milligrams) per kilogram of the animal’s body weight when given orally; the median effective dose when given intraperitoneally is 113 micromoles (~20 milligrams) per kilogram.

Clinical studies have assessed the merits of sulforaphane in a wide range of chronic and infectious diseases, including autism, aflatoxin toxicity, air pollution detoxication, cancer, cardiovascular disease, diabetes, neurodegenerative disease, Helicobacter pylori infection, and many others. Although the doses used in rodents are quite high, clinical studies have demonstrated efficacy in more reasonable dose ranges for humans. These doses varied markedly in quantity and in terms of whether they are supplied as glucoraphanin (the precursor) or sulforaphane (the end product). The median dose of glucoraphanin was 190 micromoles (~76 milligrams) and of sulforaphane was 100 micromoles (~18 milligrams). However, some clinical research has used stabilized sulforaphane in doses as high as 60 milligrams to yield a positive effect.

The authors of the review enumerate several issues that must be overcome in designing and conducting clinical studies with sulforaphane, but they stress the importance of plant-based diets as delivery modes for not only sulforaphane but other bioactive compounds that promote health. They also noted concerns that determining dose is inherently difficult in light of the differences in bioavailability of glucoraphanin and sulforaphane; translating animal data to humans poses challenges, too.

Link to full review.

Sulforaphane inhibits enzyme involved in amyloid-beta production.

Amyloid-beta is a toxic 42-amino acid peptide that clumps and forms plaques in the brain with age. Amyloid-beta is associated with Alzheimer’s disease, a progressive neurodegenerative disease and the most common cause of dementia. Findings from a new study demonstrate that sulforaphane impairs BACE1, an enzyme involved in the production of amyloid-beta.

BACE1, or beta site amyloid precursor protein cleaving enzyme 1, is produced primarily in the central nervous system. People with Alzheimer’s disease often have high levels of BACE1 in their brains.

The authors of the study set out to evaluate sulforaphane’s capacity to inhibit BACE1. They used fluorescence resonance energy transfer analysis to determine the enzyme’s activity and then calculated its kinetics. They assessed sulforaphane’s enzyme selectivity in the presence of several other enzymes and compared sulforaphane’s effects to those of resveratrol and quercetin, bioactive compounds that exert beneficial effects on human health.

They found that sulforaphane was six times more effective against BACE1 compared to resveratrol and quercetin. Sulforaphane demonstrated high affinity for BACE1 and had few off-target effects, suggesting that sulforaphane shows promise as a candidate to reduce the activity of BACE1, potentially playing a role in preventing Alzheimer’s disease.

Link to full study.

Nrf2 pathway is a major target for sulforaphane.

Nrf2 (nuclear factor erythroid 2-related factor 2) is a cellular protein that regulates the expression of antioxidant and stress response proteins. It participates in the Keap1/Nrf2/ARE biological pathway – the primary mechanism by which sulforaphane exerts its beneficial effects. A 2017 review describes the role of sulforaphane in the Keap1/Nrf2/ARE pathway and summarizes the beneficial health effects associated with the compound.

The Keap1/Nrf2/ARE pathway is a key mediator of cytoprotective responses to oxidative and electrophilic stressors. Under normal cellular conditions, Keap1 tethers Nrf2 in the cytoplasm (the region of the cell outside the nucleus), where it can be tagged and delivered for degradation. However, following exposure to stressors, Keap1 undergoes modifications that impair its ability to bind to and target Nrf2 for degradation. As a result, Nrf2 is free to travel to the nucleus, where it binds to antioxidant response elements (AREs) of DNA. AREs are sequences in the regulatory regions of genes that activate transcription of a diverse group of cytoprotective enzymes.

Isothiocyanates react with certain regions on Keap1, eliminating Keap1’s ability to target Nrf2 for degradation – effectively serving the role of stressor. Sulforaphane, an isothiocyanate derived from broccoli and broccoli sprouts, is the most potent naturally occurring inducer of Nrf2.

The authors of the review presented evidence that sulforaphane protects against carcinogenesis in models of skin, oral, stomach, colon, lung, prostate, and bladder cancer. They also reported that feeding studies involving humans and consumption of isothiocyanate-rich cruciferous vegetables have demonstrated measurable Nrf2 activity, reflected in increased levels antioxidant proteins and enzymes, including glutathione S-transferase and NQO1. Future research will inform optimal dosages and formulations for clinical trials.

Link to full review.
Watch this clip in which Dr. Jed Fahey describes the early co-discoveries of sulforaphane and Nrf2 and describes the importance of the Nrf2 pathway.