Control group

Take responsibility for your one precious life – DHEA

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This 2020 meta-analysis subject was DHEA:

“Twenty-four qualified trials were included in this meta-analysis. Statistically significant increases in serum IGF-1 levels were found only in participants who were:

  1. Women; or
  2. Supplementing 50 mg/d; or
  3. Undergoing intervention for > 12 weeks; or
  4. Without an underlying comorbidity; or
  5. Over the age of 60 years.

DHEA supplementation led to an overall increase of ~16 ng/ml in serum IGF-1 levels, as well as increases of ~23 [women] and ~20 ng/ml [age > 60]. Diseased and healthy subjects ages ranged from 20 to 72 years old.”

Discussion section explanations of the above:

  1. “Women are more susceptible to biochemical and clinical shifts caused by DHEA supplementation.
  2. The majority of investigations tested DHEA at a dose of 50 mg/d.
  3. The majority of studies were performed for > 12 weeks.
  4. Participants with no comorbidities were also older in many studies.
  5. Older patients have a natural decline in the production of IGF-1 and DHEA.

Additional rigorous RCTs are warranted to better define whether and to what extent changes in IGF-1 levels caused by DHEA supplementation are relevant for health benefits.”

https://www.sciencedirect.com/science/article/abs/pii/S0531556520302977 “Impact of dehydroepian[d]rosterone (DHEA) supplementation on serum levels of insulin-like growth factor 1 (IGF-1): A dose-response meta-analysis of randomized controlled trials” (not freely available)

More on IGF-1 from The influence of zinc supplementation on IGF-1 levels in humans: A systematic review and meta-analysis which was cited for “Previous studies have demonstrated that IGF-1 levels can be affected by several factors.”

“IGF-1 is a growth factor synthesized in the liver, and elicits a myriad of effects on health due to its participation in the GH-IGF-1 axis, where it:

  • Is involved in tissue homeostasis;
  • Has anti-apoptotic, mitogenic, anti-inflammatory, antioxidant and metabolic actions;
  • Contributes to skeletal muscle plasticity, maintenance of muscle strength and muscle mass;
  • Neural and cardiovascular protection;
  • Development of the skeleton;
  • Possesses insulin-like effects, and
  • Is a key factor in brain, eye and lung development during fetal development.

IGF-1 plays important roles in both growth and development, and its levels vary depending on age, with peaks generally observed in the postnatal period and at puberty. IGF-1 levels influence the release of GH [growth hormone] from the hypophysis [pituitary gland] via a negative feedback loop.

A rapid decrease in IGF-1 levels is registered during the third decade of life. Levels gradually decrease between the third and the eighth decade of life.”

The Group 3 “> 12 weeks” finding was reinforced by perspectives such as:

Group 4 “with no comorbidities” was narrowly defined. All of us have degrees of diseases in progress. Consider aging effects:

  • Aging as a normal disease “Aging and its diseases are inseparable, as these diseases are manifestations of aging. Instead of healthy aging, we could use the terms pre-disease aging or decelerated aging.”
  • Aging as an unintended consequence “Epigenetic ageing begins from very early moments after the embryonic stem cell stage and continues uninterrupted through the entire lifespan. Ageing is an unintended consequence of processes that are necessary for development of the organism and tissue homeostasis thereafter.”
  • Organismal aging and cellular senescence “If we assume that aging already starts before birth, it can be considered simply a developmental stage, required to complete the evolutionary program associated with species-intrinsic biological functions such as reproduction, survival, and selection.”
  • An environmental signaling paradigm of aging “The age-phenotype of a cell or organ depends on its environment and not its history. Organisms, organs, and their cells can be reset to different age-phenotypes depending on their environment.”

These perspectives are less important than what each of us choose to do about our own problems. Take responsibility for your one precious life.

Get serious about advanced glycation end products (AGEs)

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Ever heard about AGEs? Here are three papers that describe how AGEs affect humans.

First is a 2020 Italian review Common Protective Strategies in Neurodegenerative Disease: Focusing on Risk Factors to Target the Cellular Redox System:

“Neurodegenerative disease is an umbrella term for different conditions which primarily affect the neurons in the human brain. Currently, neurodegenerative diseases are incurable, and the treatments available only control the symptoms or delay the progression of the disease.

Neurotoxicity can be induced by glycation reactions. Since glycation is a nonenzymatic process, proteins characterized by a slow turnover are those that more easily accumulate AGEs.

Methylglyoxal (MG) can occur as glycolysis by-product, but it is also present in foods (especially cooked and baked), beverages (mainly those fermented), and cigarette smoke, and it is considered the most potent precursor of AGE formation. More than 20 different AGEs have been identified in foods and in human tissues.

AGE accumulation, oxidative stress, and inflammation are related to AGE ability to bind specific receptors called RAGE. RAGE expression increases during aging, cancer, cardiovascular diseases, AD [Alzheimer’s], PD [Parkinson’s], and other neurodegenerative diseases.”

A 2015 study by some of the same authors Antiglycative activity of sulforaphane: a new avenue to counteract neurodegeneration? was cited for a treatment in addition to changing one’s diet to be AGE-less.

“When MG production is increased by high glucose or oxidative stress, glycated proteins accumulate in the brain and lead to glycative stress, playing a fundamental role in the establishment of different neurodegenerative disorders.

Our results indicated that SF [sulforaphane] counteracts ROS by two possible mechanisms of action: an increase of intracellular GSH [glutathione] levels and an enhancement of MG-detoxification through the up-regulation of the glyoxalase (GLO1) systems. GLO1 up-regulation is mediated by the transcription factor Nrf2. SF has been demonstrated to activate Nrf2.

Another mechanism by which SF exerts its neuroprotective activity against MG-induced glycative damage is the modulation of mitogen-activated protein kinase (MAPK) signaling pathways involved in apoptotic cell death. All MAPK signaling pathways are activated in AD.

Brain-derived neurotrophic factor (BDNF) is associated with neuronal survival through its interactions with the tyrosine receptor kinase B (TrkB) and p75 cellular receptors. BDNF expression levels are reduced in the brain of AD patients. SF pre-treatment, before MG addition, not only further increased BDNF levels, but also significantly induced TrkB protein levels reverting MG negative effect on this receptor.

SF totally reverts the reduction of glucose uptake caused by MG exposure. SF can be defined as a multitarget agent modulating different cellular functions leading to a pro-survival frame of particular importance in the prevention / counteraction of multifactorial neurodegenerative diseases.”

A 2020 review Non-enzymatic covalent modifications: a new link between metabolism and epigenetics investigated glycation:

“Non-enzymatic covalent modifications (NECMs) by chemically reactive metabolites have been reported to manipulate chromatin architecture and gene transcription. Unlike canonical post-translational modifications (PTMs), NECMs accumulate over time and are much more dependent on the cellular microenvironment.

A. Guanine residues in DNA and RNA can undergo methylglyoxal glycation, thereby inducing DNA and RNA damage. This DNA damage has few corresponding repair pathways.

B. Histones are primary glycation substrates because of their long half-lives and abundant lysine and arginine residues. Histone glycation was found to induce epigenetic dysregulation through three distinct mechanisms:

  1. Competition with essential enzymatic PTMs for sites (e.g., glycation adducts replace H3K4me3 and H3R8me2);
  2. Changing the charge states of histone tails and subsequently affecting the compaction state of the fiber; and
  3. Altering three-dimensional chromatin architecture by inducing both histone-histone and histone-DNA crosslinking.

Epigenetic impacts of histone glycation were shown to be dependent on sugar concentration and exposure time. Histone and DNA glycation may lead to long term epigenetic impacts on immune responses.

C. Glycation of multiple lysine residues of NRF2 inhibits its oncogenic function. Sugar molecules can influence epigenetic events through glycation of transcription factors and/or their associated regulatory proteins.”

The Transcription factor glycation section referenced a 2011 paper Regulation of the Keap1/Nrf2 system by chemopreventive sulforaphane: implications of posttranslational modifications:

“Nrf2 mRNA level is unaffected by treatment with sulforaphane, suggesting that cellular expression of Nrf2 protein is posttranscriptionally regulated. Posttranslational modifications of Keap1 and Nrf2 proteins seem to play an important role in the regulation of ARE‐dependent gene expression.”

“Neurodegenerative diseases are incurable?” Take responsibility for your own one precious life.

Other curated AGEs papers include:

Broccoli sprout synergies

gettingwell4 4-5 stars Advanced knowledge, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress , , , ,

I was asked for examples of broccoli sprout synergies with supplements mentioned in Week 19 of Changing to a youthful phenotype with broccoli sprouts. I take supplements and broccoli sprouts together an hour or two before meals to keep meal contents from lowering sulforaphane bioavailability. Sulforaphane peaks in plasma between 1 and 2 hours after ingestion.

sulforaphane peak plasma

I started splitting broccoli sprout doses after reading the first study of A pair of broccoli sprout studies. The second study was Untargeted metabolomic screen reveals changes in human plasma metabolite profiles following consumption of fresh broccoli sprouts.

Those subjects ate only “a single dose of fresh broccoli sprouts (providing 200 μmol SFN equivalents) at 8 AM on study day 1.” A 200 μmol amount of sulforaphane is a 35 mg weight.

For comparison, my daily consumption is a worst-case 52 mg sulforaphane from microwaving 131 g of 3-day-old broccoli sprouts per Estimating daily consumption of broccoli sprout compounds. Every day for 22 weeks now. 🙂

The second study’s measurements through 48 hours produced this informative graphic and text:

“Of the features we identified using metabolite databases and classified as endogenous, eleven were significantly altered.

  • Glutathione (GSH) – a major intracellular antioxidant that conjugates with SFN during metabolism – was significantly decreased in plasma at 6, 12 and 24 hours following sprout intake.
  • GSH precursors glutamine (3 and 24 hours) and cysteine (12 and 24 hours) also decreased.
  • We observed significant decreases in dehydroepiandrosterone (DHEA) at 3, 6 and 12 hours.
  • Decreases in fatty acids reported here suggest that even a single dose of broccoli sprouts may alter plasma lipids in healthy adult populations.

While this study focuses largely on potential effects of SFN, broccoli sprouts contain many other bioactive components (e.g., indoles) that could be responsible for our observations as well as additional health benefits.”

Supplements I take twice daily with broccoli sprouts:

  • 1 gram L-glutamine for replenishment and other purposes;
  • 25 mg DHEA to replenish and other effects;
  • 15 mg then 50 mg zinc, which has a role in GSH metabolism;
  • 500 mg glucosamine (anti-inflammatory, crosstalk with Nrf2 signaling pathway);
  • 500 mg acetyl-L-carnitine (induces Nrf2-dependent mitochondrial biogenesis); and
  • 1400 IU then 2000 IU Vitamin D. A major portion of its effects is Nrf2 activation, like sulforaphane. A virtuous circle develops when taken with broccoli sprouts in that the Vitamin D receptor is a Nrf2 target gene inducible by sulforaphane, which then upregulates Nrf2 expression levels.

One of the things eating Boring Chicken Vegetable Soup twice a day does is replenish cysteine. I eat that and steel-cut oats (another cysteine source) separately from broccoli sprouts.

I take 1 gram flax oil with breakfast and dinner instead of with broccoli sprouts. Haven’t found relevant research on whether broccoli sprout compounds decrease omega-3 polyunsaturated alpha linolenic acid C18:3 as they do these six endogenous fatty acids.

Both studies investigated effects of fresh broccoli sprouts. Timing of their measured decreases and increases are different for me because I microwave broccoli sprouts up to but not exceeding 60°C (140°F).

A section of Microwave broccoli seeds to create sulforaphane highlighted metabolic differences among fresh broccoli sprouts, microwaved broccoli sprouts, and broccoli sprout supplements.

“A metabolic profile resulting from my current practices is probably between the Sprout and BSE (broccoli sprout extract) divided-dose statistics:

  1. Sulforaphane intake is greater than eating raw broccoli sprouts because microwaving 3-day-old broccoli sprouts creates sulforaphane in them before eating.
  2. Sulforaphane uptake from microwaved broccoli sprouts is quicker than eating raw broccoli sprouts. It may not be as immediate as taking sulforaphane supplements, which are usually powders.
  3. Sulforaphane dose from microwaved broccoli sprouts is less dependent on an individual’s metabolism than eating raw broccoli sprouts.
  4. Sulforaphane release from microwaved broccoli sprouts continues on to the gut as does eating raw broccoli sprouts. Sulforaphane release from supplements may not per Does sulforaphane reach the colon?.”

Metabolism of broccoli sprout glucoraphanin and other glucosinolates that aren’t preferentially hydrolyzed by microwaving and thorough chewing is assisted in the gut twice a day by:

  • 6 billion IU acidophilus; and
  • 750 mg fructo-oligosaccharides.

See Treating psychopathological symptoms will somehow resolve causes? for updates.

Take responsibility for your one precious life – Trained innate immunity

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This 2020 review subject was the normal progression of our immune systems:

“Age-related alterations in the immune system result in high susceptibility to infections, increased risk of hospitalization and mortality. Defects in adaptive immunity underlie the markedly low vaccine efficiency in the elderly. Despite reduced cellular functions, a systemic increase in inflammatory markers, so-called inflammaging, is observed in aged individuals.

Trained immunity is a newly emerging concept that showed that innate immune cells possess non-specific immunological memory established through epigenetic and metabolic reprogramming upon encountering certain pathogenic stimuli.

Novel approaches targeting innate immunity to improve host responses are crucial to evade the consequences of the aged immune system. It is an emerging concept that innate immune cells can manifest memory-like properties that are not antigen-specific and exhibit enhanced responsiveness upon later challenges with heterologous stimuli. Whether trained immune responses change as people age is yet to be explored.”

https://academic.oup.com/intimm/advance-article/doi/10.1093/intimm/dxaa052/5885077 “Overcoming immune dysfunction in the elderly: trained immunity as a novel approach”

Previous papers by this review’s corresponding coauthor were curated in:

There’s no reason to rely entirely on the review’s elaborate vaccination schemes to develop trained immunity. Take responsibility for your one precious life and Train your immune system every day!

Sleep

gettingwell4 2-3 stars Required further work, Acetylcholine, Amygdala, Beliefs, Brainstem, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress, Testosterone, Vasopressin , , , , , , ,

If you can stand the woo of two Californians trying to outwoo each other, listen to these five podcasts with a sleep scientist.

https://peterattiamd.com/matthewwalker1/

“Ambien, sedation, hypnotives, are not sleep.

Sleep is a life support system. It’s the Swiss army knife of health.

Lack of sleep is like a broken water pipe in your home that leaks down into every nook and cranny of your physiology.

Sleep research is not being transmitted to clinical practice.”

I live on the US East Coast. Hyperbole in normal conversations outside of urban centers is an exception.

It’s different on the West Coast. For example:

  • Interviewer assertions regarding heart rate variability should be compared and contrasted with Dead physiological science zombified by psychological research evidence that:

    “A broad base of further evidence was amassed within human cardiac, circulatory, and autonomic physiology such that the hypotheses do not work as described.”

  • Interviewer favorable comments for MDMA (Ecstasy) “to deal with issues of underlying trauma, anxiety, and depression.”

Eat broccoli sprouts for your skin!

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Memory, Stress ,

This 2020 Swiss review subject was the interaction of Nrf2 activators and skin:

“The electrophile and Nrf2 activator dimethyl fumarate (DMF) is an established and efficient drug for patients suffering from the common inflammatory skin disease psoriasis. DMF is being tested for pharmacological activity in several other inflammatory skin conditions.

dmf

Psoriasis is a chronic inflammatory skin disease affecting 2–4% of the population and plaque psoriasis is the most common type, affecting about 90% of all patients. As about 30% of all patients suffer from moderate and severe psoriasis, there is a strong need for efficient systemic treatment options with few side effects.

SFN [sulforaphane] blocks NF-κB activity by several mechanisms. SFN oxidizes IκB, thereby inhibiting its phosphorylation and downstream NF-κB activation, but also targets specific cysteine residues of p50/p65, causing a reduction in DNA binding.

More indirect effects have also been suggested. SFN induces HO-1 expression via Nrf2, which in turn inhibits NF-κB. The isothiocyanate can also react with and oxidize components of cellular redox buffers, such as glutathione and thioredoxin, which are required to retain NF-κB’s DNA-binding capacity.

NLRP3 is believed to be critically involved in common diseases, whereas its role in immunity is rather minor. The mechanisms underlying NLRP3 inflammasome activation are of high medical interest.

Electrophiles can directly inhibit inflammasome activation. SFN inhibits activation of NLRP3 in the absence of NRF2 expression in a very fast manner, suggesting that transcriptional effects are not relevant for NLRP3 inhibition. SFN inhibits NLRP3 even in KEAP1 knockout cells.

All these results demonstrate that electrophiles can inhibit the inflammasome pathway in a direct manner, perhaps via the modification of reactive cysteine residues of inflammasome proteins or those which regulate activation of these complexes.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072181/ “Electrophiles against (Skin) Diseases: More Than Nrf2”

These reviewers focused on a pharmaceutical. Read this article for progress made on a generic:

“Biogen is expected to appeal this ruling against its Tecfidera patent protection, which is not due to expire until 2028. Its list price is reported to be about $2,026 for a two-week (14 day) supply at 120 mg.

‘The District Court decision clears the legal pathway for us to bring our dimethyl fumarate product to market, and we are working with the FDA to accelerate our regulatory approval target action date, which currently is November 16.'”

Broccoli or Sulforaphane: Is It the Source or Dose That Matters? listed 15 mouse studies and 4 human studies of sulforaphane treatments of skin diseases in Supplementary Material Table S3.

From Novel Nrf2 activators from microbial transformation products inhibit blood–retinal barrier permeability in rabbits:

“The cysteine residue of sulforaphane works as a weak electrophile and it interacts with cysteine residues of Keap1. Dimethyl fumarate is also a weak electrophile.

Nrf2 activity was evaluated by NQO1 induction activity in Hepa1c1c7 cells. RS9 was the most potent and the concentration needed to double (CD) the specific Nrf2 activity was 0.2 nM. The CD values for bardoxolone methyl, sulforaphane and dimethyl fumarate were 0.9 nM, 154.4 nM and 13.3 μM respectively.”

1. This review didn’t mention dimethyl fumarate’s NQO1 induction CD value because..? It’s one of Nrf2 signaling pathway’s main studied parameters, along with HO-1. For example, from Autism biomarkers and sulforaphane:

“This time point was chosen based on our earlier observations of kinetics of upregulation of Nrf2-dependent genes by SF, and was expected to capture increased mRNA production of both very fast (HO-1) and relatively slow (NQO1) responders.”

2. What about adverse effects? From Sulforaphane and RNAs:

“DMF is the most successful Nrf2 activator, FDA-approved in 2013 for the treatment of relapsing remitting multiple sclerosis. However, DMF causes leukopenia and other side-effects.

Bardoxolone cleared Phase II clinical trials for the treatment of advanced chronic kidney disease and type 2 diabetes mellitus, but was halted in Phase III trials due to cardiovascular concerns.”

3. What about prevention mechanisms for skin problems? Skin care isn’t just cancer prevention.

So – what can a person do to treat an inflammation problem in our largest organ, our skin?

  • Pay $2,026 every two weeks to take a daily 120 mg dose of a brand name pharmaceutical?
  • Wait around for some hypothetical future “development of new tailor-made molecules and drugs for the many inflammatory conditions which are associated with Nrf2, NF-κB and inflammasomes”?
  • Try other treatments that just address symptoms, not causes?

Or eat daily clinically-relevant broccoli sprout dosages for < $500 a year?

Week 19 of Changing to a youthful phenotype with broccoli sprouts

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory, Stress

To follow up Week 18:

1. Continued attention to broccoli sprout gardening details was this week’s theme. The 12-6-6 schedule had an extra rinse during lunch time.

I stopped when the 8/3 evening batch smelled bad. Broccoli sprouts don’t do well with too much moisture.

I didn’t have this problem on a 12-12 schedule of two rinses. But I also didn’t have good yields.

I switched to an 8-8-8 schedule, and the problem didn’t recur. However, intervals were 5:00 a.m., 1:00 p.m., and 9:00 p.m. That led to eating broccoli sprouts too early and too late, and disrupting my sleep.

8-8-8 also didn’t produce optimal yields. The top two yields this week were both on 8/5. Those two batches started on 8/2, and apparently benefited from a 12-6-6 schedule during their initial germination stages.

I switched back to 12-6-6 on 8/7 with an extra step of rinsing my strainer and teaspoon between batch rinses. Not sure this step addresses whatever happened on 8/3, but it protects against one batch’s problems spreading to other batches. I’ll continue 12-6-6 unless I cause moisture problems, in which case I’ll return to a 12-12 routine.

The (65.5 gram x 2) = 131 g daily average of this week’s broccoli sprouts has been factored into Estimating daily consumption of broccoli sprout compounds numbers for broccoli seeds, sprouts and their compounds. Some worst-case scenarios change to evidenced estimates, such as consuming 52 mg sulforaphane daily by microwaving 131 g of 3-day-old broccoli sprouts.

I’ll update the many blog posts that reference these estimates. Most of them can be recognized from strikethrough typography.

2. During the 8-8-8 schedule I ate microwaved broccoli sprouts with supplements and sauerkraut instead of during a meal. I wondered if meal composition made any difference to broccoli sprout compounds. My meals are breakfast started with 1/2 cup (82 grams) of steel-cut oats, Boring Chicken Vegetable Soup for dinner, and leftover soup at lunch.

A 2018 Netherlands study Bioavailability of Isothiocyanates From Broccoli Sprouts in Protein, Lipid, and Fiber Gels found:

“Compared to the control broccoli sprout, incorporation of sprouts in gels led to lower bioavailability for preformed sulforaphane and iberin.”

IAW, eating protein, fats, and fiber along with microwaved broccoli sprouts wouldn’t help. So I’ll keep eating them with supplements for synergies* but not immediately before or after meals.

A 2018 review with some of the same researchers Isothiocyanates from Brassica Vegetables-Effects of Processing, Cooking, Mastication, and Digestion offered one possible explanation for protein acting to lower broccoli sprout compounds’ bioavailability:

“In vitro studies show that ITCs can potentially react with amino acids, peptides, and proteins, and this reactivity may reduce the ITC bioavailability in protein‐rich foods. More in vivo studies should be performed to confirm the outcome obtained in vitro.”

3. I mix in homemade sauerkraut when I eat microwaved broccoli sprouts. It helps ensure that I thoroughly chew sprouts. Wouldn’t expect anyone else to like unsalted sauerkraut.


Continued with Week 20 of Changing to a youthful phenotype with broccoli sprouts.

*See Broccoli sprout synergies for details.

Sulforaphane clinical trials and COVID-19

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A plethora of articles have been published this year on how researchers’ favorite topics can / may / should / could / will fix COVID-19. This one was different in that relevant clinical trials were both completed and already underway before a Madness of Crowds behavioral contagion infected us:

“It is crucial to understand the most appropriate context for introducing an anti-inflammatory therapy to complement an antiviral therapy. Such therapy must control inflammation without altering the ability of the host to mount an efficient adaptive immune response against the virus.

We propose that boosting endogenous cellular defenses by targeting the cytoprotective transcription factor Nrf2 (gene name NFE2L2) will promote the resolution of COVID-19 associated inflammation and also restore redox homeostasis and facilitate tissue repair.

The isothiocyanate sulforaphane (SFN) is the most potent naturally occurring NRF2 activator, with well-documented antioxidant and anti-inflammatory effects. The high bioavailability of SFN makes it an excellent candidate for alleviating excessive anti-inflammatory responses and protecting the lungs.

Even though Nrf2 is the primary mediator, additional factors contribute to the anti-inflammatory effects of SFN. SFN inhibits NF-κB, inhibitor of NF-κB kinase subunit β (IKKβ), and STAT3.

By regulating the endogenous cytoprotective systems, Nrf2 may have a more physiological role in achieving a balance between the beneficial and adverse effects of inflammation. Nrf2 inhibits IL-6 and IL-1β gene expression.

Antioxidant and cytoprotective effects of Nrf2 activation are long-lasting and persist for several days after inducer elimination. They are mediated by enzymes that, in contrast to small molecules, have long half-lives and are not consumed, and are instead regenerated during the reactions which they catalyze.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359808/ “Can Activation of Nfr2 Be a Strategy against COVID-19?”

The paper also documented in vitro, animal, and non-clinical human Nrf2 activator studies relevant to causes and effects.

Sulforaphane and RNAs

gettingwell4 2-3 stars Required further work, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Stress , , ,

This 2020 Texas review subject was long non-coding RNAs:

“We review the emerging significance of long non-coding RNAs (lncRNA) as downstream targets and upstream regulators of the Nrf2 signaling pathway, a critical mediator of diverse cellular processes linked to increased cell survival.

It is believed that more than 3% of human genes are regulated by the Nrf2/Keap1 pathway. In addition to the classical cytoprotective and oxidative stress response genes transactivated by Nrf2, emerging evidence suggests a role for non-coding transcript regulation at the level of noncoding RNAs, [which] far outnumber protein-coding genes in the human genome.

One important distinction between miRNAs and lncRNAs is that the latter are often species-specific, meaning that a human lncRNA typically cannot be studied in the mouse or rat, and vice versa.

Sulforaphane (SFN) acts via multiple mechanisms to modulate gene expression, including the induction of Nrf2-dependent signaling. In addition to the established canonical targets of Nrf2, such as NQO1 and HMOX1, SFN altered the expression of multiple lncRNAs.

Given that SFN induces NMRAL2P [a lncRNA pseudogene] and several other lncRNAs in colon cancer cells, further studies are warranted on their respective roles as upstream regulators and/or downstream targets of Nrf2 signaling.

Pharmacological modulation of Nrf2 is considered a viable strategy against chronic conditions that are accompanied by oxidative stress and inflammation:

  • DMF [dimethyl fumurate] is the most successful Nrf2 activator, FDA-approved in 2013 for the treatment of relapsing remitting multiple sclerosis. However, DMF causes leukopenia and other side-effects.
  • Bardoxolone cleared Phase II clinical trials for the treatment of advanced chronic kidney disease and type 2 diabetes mellitus, but was halted in Phase III trials due to cardiovascular concerns.
  • SFN is relatively unstable at room temperature.

We used reported bioinformatics approaches to search for putative ARE [antioxidant response element] sequences among the entire set of 16,000+ annotated human lncRNAs. 13,285 promoter regions contained one or more potential binding sites for Nrf2.”

https://www.sciencedirect.com/science/article/pii/S0304383520303670 “Emerging crosstalk between long non-coding RNAs and Nrf2 signaling”

This study hyped lncRNAs in that only 7 have been validated as Nrf2 targets, and 8 validated as Nrf2 regulators. For regulators, “protein and/or miRNA interacting partners are yet to be fully corroborated” as well.

Also, there’s no need for a “SFN is relatively unstable at room temperature” problem. Just create sulforaphane right before consuming it.

Twice a day I microwave an average 65.5 grams of 3-day-old broccoli sprouts immersed in 100 ml water with a 1000W microwave on full power for 35 seconds to ≤ 60°C. After microwaving I transfer broccoli sprouts to a strainer, and wait five minutes to allow further myrosinase hydrolization of glucoraphanin and other glucosinolates into sulforaphane and other healthy compounds.

Reprogram inflammation with β-glucan

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory, Stress

This 2020 French human cell study found:

“Exposure of mononuclear phagocytes to β-glucan contributes to the induction of innate immune memory, which is associated with long-term epigenetic, metabolic, and functional reprogramming. We investigated how preincubation of human monocytes with particulate β-glucan affects the biological response of macrophages following NLRP3 inflammasome activation.

Upon infection or cellular damage, NLRP3 assembles into a multiprotein inflammasome complex leading to the release of IL-1β. However, NLRP3 inflammasome activity can also be detrimental to the host, and its aberrant chronic activation is associated with severe pathologies.

β-Glucan is a safe molecule present in food products and already widely used in food supplementation. Although β-glucan–induced innate memory is associated with a nonspecific protective effect against infections, the role of this functional reprogramming in autoinflammatory disorders is unknown.

Because of the administration frequency and conservation needs, IL-1β–targeted therapy is invasive, complex, and also costly. In addition, IL-1β, an acute-phase protein, is crucial for effective immune responses to infection, and inhibitors targeting IL-1β may lead to unintended immunosuppressive effects in addition to preventing NLRP3 inflammasome activity in itself.

Targeting the origin of the disease, i.e., NLRP3, would represent the best therapeutic strategy. Most of these candidate drugs directly interact with NLRP3, but none seems to regulate the early activation events upstream of NLRP3 inflammasome assembly.

β-Glucan acted upstream of the NLRP3 inflammasome. β-glucan–induced innate immune memory represses IL-1β–mediated inflammation and support its potential clinical use in NLRP3-driven diseases.”

https://www.jci.org/articles/view/134778 “β-Glucan–induced reprogramming of human macrophages inhibits NLRP3 inflammasome activation in cryopyrinopathies”

This study came closer to addressing causes than others with:

“Targeting the origin of the disease would represent the best therapeutic strategy.”

It’s apparently too recent with a July 27th published date to make it onto https://www.betaglucan.org/i-p/, but earlier β-glucan inflammation studies may be found there.

Topical sulforaphane protects skin

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This 2020 Rutgers rodent study explored topical application of sulforaphane to prevent UVB-induced skin carcinogenesis:

“We investigated the transcriptomic and DNA methylomic changes during tumor initiation, promotion, and progression and its impact and reversal by sulforaphane (SFN). The production of ROS and inflammation are closely linked to UVB-induced carcinogenesis. SFN protects skin cells from UVB-induced damage mainly through promoting anti-inflammatory, antioxidative and anticancer pathways.

We observed the changes after 2, 15 and 25 weeks of UVB exposure, which would represent the three different stages of skin cancer development. After 2 weeks of UVB exposure, we did not observe any obvious tumors in the UVB group. But after 15 weeks of UVB exposure, some obvious tumors were observed in the skin.

After 15 weeks of UVB treatment in epidermal tissue, the difference between the UVB group and the control group was significantly more than that between the SFN group versus the UVB group. SFN appears to have better cancer-protective effects in earlier time points (weeks 14 and 20) than later time point (week 24). At weeks 20, SFN had significantly fewer tumors with decreased total tumor volume and tumor number.

SFN plays a highly regulatory role in various signaling pathways during UVB irradiation. SFN impacts UVB-induced alterations of DNA methylation profiles, and importantly, SFN treatment attenuates some of these DNA methylation changes. We found a subset of genes associated with SFN treatment, and the relevant changes in gene expression may be driven by promoter CpG methylation status.”

https://cancerpreventionresearch.aacrjournals.org/content/13/6/551 “Epigenome, Transcriptome, and Protection by Sulforaphane at Different Stages of UVB-Induced Skin Carcinogenesis” (not freely available)

We’re getting closer to using epigenetic clocks in sulforaphane studies. This study ignored the 2018 A multi-tissue full lifespan epigenetic clock for mice in favor of their homegrown DNA methylation measurements.

A search of ClinicalTrials.gov didn’t turn up directly relevant human studies.

Eat sauerkraut today!

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Stress , ,

This 2017 Spanish article reviewed health benefits of sauerkraut:

“During cabbage shredding and fermentation, a disruption of cabbage cells occurs, and GLS [glucosinolates] are hydrolyzed by myrosinase enzyme to a variety of GLS breakdown products. In particular, glucobrassicin is hydrolyzed into indol-3-carbinol (I3C) by myrosinase.

As the pH decreases during cabbage fermentation, I3C reacts nonenzymatically with ascorbic acid to yield ascorbigen (ABG). Studies have shown that ABG is the main GLS breakdown compound in sauerkraut, and it is present at levels between 3 and 18 μmol/100 g fw.

The antioxidant activity observed for sauerkraut in all studies was higher than that observed in raw cabbage.

It has been reported that doses between 53 and 150 μmol of ITCs [isothiocyanates] are enough to display anticarcinogenic effects. Taking into account that the content of ITCs in sauerkraut is in the range 22 μmol/100 g fw, it could be assumed that a weekly consumption of 200–250 g of sauerkraut would provide effective ITC doses to exert cancer chemopreventive effects.

Many studies reported that LAB [lactic acid bacteria] isolated from sauerkraut are potential probiotics.”

https://www.sciencedirect.com/science/article/pii/B9780128023099000248 “Sauerkraut: Production, Composition, and Health Benefits” (not freely available)

This introductory article presented interesting facts, but oversold sauerkraut. Dose and other conditional dependencies in order to achieve health and disease prevention benefits seemed to be beyond its scope.

A more considered view was offered in Fermented Food and Non-Communicable Chronic Diseases which referenced this article:

“Clinical data about the effects of sauerkraut on the human organism, health and disease are scarce. There is knowledge concerning particular compounds in sauerkraut and their impacts on diseases; however, a literature search revealed mostly cell line or rat experiments with very limited conclusions for humans.”

Earlier this month I started eating refrigerated sauerkraut twice a day with microwaved broccoli sprouts. I mix in three heaping teaspoons each time, and finish a 50 oz (1418 g) container in a week.

The mixture tastes better than just microwaved broccoli sprouts. It requires more chewing, which assists myrosinase hydrolization of broccoli sprout glucosinolates into sulforaphane and other healthy compounds.

Although sauerkraut isn’t a primary source, there may be beneficial amounts of probiotics etc. that increase what I get with broccoli sprouts and supplements.

I also started making my own sauerkraut using the commercial product’s juice as a starter. I add garlic but not salt. No results yet.

Transgenerational epigenetic inheritance of epimutations

gettingwell4 5+ stars Premium, Epigenetics, Memory, Stress , , , , ,

My 600th curation is a 2020 rodent study from Dr. Michael Skinner’s labs at Washington State University:

“Numerous environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. Alterations in the germline epigenome are necessary to transmit transgenerational phenotypes.

In previous studies, the pesticide DDT and the agricultural fungicide vinclozolin were shown to promote the transgenerational inheritance of sperm differential DNA methylation regions, non-coding RNAs and histone retention, which are termed epimutations. The current study was designed to investigate the developmental origins of the transgenerational differential histone retention sites (called DHRs) during gametogenesis of the sperm.

In addition to alterations in sperm DNA methylation and ncRNA expression previously identified, the induction of DHRs in the later stages of spermatogenesis also occurs. This novel component of epigenetic programming during spermatogenesis can be environmentally altered and transmitted to subsequent generations.

While the DHR may be consistent and present between the stages of development, the histone modifications may be altered. Several of the core histone retention sites absent in the DHRs had altered histone methylation. This adds a level of complexity to the potential role of histone retention in that it may be not only the retention, but also the alterations in histone epigenetic modifications.

The DHRs had positional associations with genes and the major functional categories were signaling, metabolism and transcription.

In the event the embryo stem cell population has a modified epigenetics and corresponding transcriptome, then all somatic cells derived from the stem cell population will have an altered cascade of epigenetic and gene expression programming to result in adult differentiated cells with altered epigenetics and transcriptomes. Previous observations have demonstrated in older adult human males alterations in histone retention develop and are associated with infertility.

Similar observations have also been provided for the development of differential DNA methylation regions (DMRs) induced by environmental toxicants such as DDT and vinclozolin. Since DHRs have a similar developmental programming, other epigenetic processes such as ncRNA are also anticipated to be similar.”

https://www.sciencedirect.com/science/article/pii/S0012160620301834 “Developmental origins of transgenerational sperm histone retention following ancestral exposures”

This study, like its dozens of predecessors performed year after year by this research facility, provided evidence for mechanisms of epigenetic transgenerational inheritance. The studied F3 generation members were great-grand-offspring, the first generation to have no direct exposure to DDT and vinclozolin.

As pointed out in A compelling review of epigenetic transgenerational inheritance:

“During the 1950s, the entire North American population was exposed to high levels of the pesticide DDT, when the obesity rate was < 5% of the population. Three generations later, the obesity frequency in North America is now ~45% of the population.”

There are varieties of mischaracterizations and hand-waving denials of epigenetically-inherited diseases. People don’t want to hear about and read proof that something we did or experienced disfavored our children, who unwittingly passed resultant problems on to their children, and which furthered on to their children’s children.

Take responsibility for your one precious life – β glucan

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory, Stress ,

From the main page of https://www.betaglucan.org/, a compilation for researchers:

“Beta Glucan extracted from yeast cell wall, can be a potent immune response potentiator and modulator. A common test to determine a glucan’s immune response potentiation effectiveness is the measure of the degree to which a glucan increases the nitric oxide burst, a pathogen killing agent.

Determinants of immune response activation and effectiveness are beta glucan source, processing, sizing and uniformity of beta glucan particles ingested. Particle size of 1-4 microns is optimum. Ingestion is optimized to prevent reaggregation.”

A sample of research:

“The tested (and suggested) daily dose remains in the range of 100–500 mg for stimulation of the immune system, whereas for a decrease in cholesterol levels a daily dose of 3 g is recommended.

Glucan supplementation prevents or even treats metabolic syndrome and decreases insulin resistance, dyslipidemia, and obesity. Glucan supplementation is a highly promising and inexpensive method of treatment for chronic respiratory problems.

Reactions known to be influenced by glucan are represented in white, reactions where glucan has no confirmed effects are shown in black.”

https://www.mdpi.com/1420-3049/24/7/1251/htm “Beta Glucan: Supplement or Drug? From Laboratory to Clinical Trials”

“Supplementation with glucan and vitamin D resulted in significant increase of vitamin D levels, improvements of HDL levels, and strong decrease of the total level of cholesterol.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897984/ “Effects of β-glucan and Vitamin D Supplementation on Inflammatory Parameters in Patients with Diabetic Retinopathy”

“β-glucan inhibits tumor growth through induced systemic tumor-antigen specific T cell response, increased activity of T-cells in tumor, and decreased number of tumor-caused immunosuppressive cells. Sulforaphane inhibits CRC [colorectal cancer] carcinogenesis by modulating Nrf2 activity and inhibition of HDAC enzymes.

In a women’s health initiative prospective cohort during their 11.7-year follow up of dietary fiber and omega-3, -6 fatty acids, the results pointed out a reduced incidence of CRC for the association between a low dose of soluble fiber, a high dose of insoluble fiber, and a high dose of EPA and DHA.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321468/ “Chemoprevention of Colorectal Cancer by Dietary Compounds”

I first curated the above review and graphic in Train your immune system every day! 12 days into a self-quarantine after coming back from Milano, Italy, Monday, February 24, 2020. There’s a substantial probability that my traveling companion and I were exposed to COVID-19.

Yet neither of us had any symptoms then or since. My β-glucan, Vitamin D3, and zinc amounts were the same as described in that post, in Take responsibility for your one precious life – Vitamin D3, and in Take responsibility for your one precious life – Zinc.

Take responsibility for your one precious life – Vitamin D3

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Immune system, Memory, Stress , , , , , , ,

Where to start among 6,489 studies and reviews published during the past five years, results from a PubMed search of “dihydroxyvitamin D3.” How about:

“Vitamin D plays a fundamental role in body calcium and phosphorous homeostasis, ensuring proper functioning of the skeletomuscular system. Pleiotropic activities include:

  • Anti-inflammatory and immunomodulatory properties (predominantly downregulation of adaptive and upregulation of innate immunity);
  • An important role in reproduction, pregnancy, placental functions and fetal and child development;
  • Important in neurodevelopment as well as in the functioning of the adult central and peripheral nervous system;
  • Regulation of global metabolic and endocrine homeostasis and the functions of different endocrine organs, as well as in the functioning of the cardiovascular system;
  • Inhibits malignant transformation, tumor progression and has anti-cancer properties on a variety of tumors;
  • Formation of the epidermal barrier and hair cycling; and
  • Ameliorating effects on skin cancer and on proliferative and inflammatory cutaneous diseases.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342654/ “The serum vitamin D metabolome: What we know and what is still to discover”

Or maybe:

“A study in 6,275 American children and adolescents aged 1–21 years showed that 61% were 25-(OH)D3 insufficient and 9% deficient. In adults, up to 40% are 25-(OH)D3 insufficient and 6% deficient.

Once adequate vitamin D values are reached, to further preserve adequate vitamin D levels in adults, the IOM [Institute of Medicine] recommends a daily dose of 600 IU per day, while the Endocrine Society recommends a dose of 600–2000 IU per day (according to the amount of sunlight the individual is exposed to). There seems to be no additional health benefit in doses higher than 4000 IU/day.

Vitamin D supplementation was protective against acute respiratory tract infections in a 25-(OH)D3 deficient population, especially in those receiving daily or weekly supplementation. However, in children this protective effect could not be reproduced.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281985/ “Vitamin D’s Effect on Immune Function”

Not to forget Advanced glycation end products alter steroidogenic gene expression by granulosa cells: an effect partially reversible by vitamin D:

“This study suggests that there is a relationship between AGEs (advanced glycation end products) and their receptors (RAGE and sRAGE) with vitamin D. Understanding the interaction between AGEs and vitamin D in ovarian physiology could lead to a more targeted therapy for the treatment of ovarian dysfunction.”

Or similarities to broccoli sprouts’ main effect of Nrf2 signaling pathway activation:

“1,25(OH)2D3 plays a role in delaying aging by upregulating Nrf2, inhibiting oxidative stress and DNA damage, inactivating p53‐p21 and p16‐Rb signaling pathways, and inhibiting cell senescence and SASP.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516172/ “1,25‐Dihydroxyvitamin D exerts an antiaging role by activation of Nrf2‐antioxidant signaling and inactivation of p16/p53‐senescence signaling”

Why do we insist on giving ourselves non-communicable diseases?

I recently paid $22.53 after tax for a nearly two-year supply:

A better use of one’s money would be..?

My June 2020 serum 25-OH Vitamin D measurement was 76 on a scale of 0 to 100 from taking a total of 3,400 IU daily. It’s fat-soluble, so I take it along with 1 gram flax oil each time.

Take responsibility for your own one precious life.