Taurine week #7: Brain

Finishing a week’s worth of 2022 taurine research with two reviews of taurine’s brain effects:

“We provide a overview of brain taurine homeostasis, and review mechanisms by which taurine can afford neuroprotection in individuals with obesity and diabetes. Alterations to taurine homeostasis can impact a number of biological processes such as osmolarity control, calcium homeostasis, and inhibitory neurotransmission, and have been reported in both metabolic and neurodegenerative disorders.

Models of neurodegenerative disorders show reduced brain taurine concentrations. On the other hand, models of insulin-dependent diabetes, insulin resistance, and diet-induced obesity display taurine accumulation in the hippocampus. Given cytoprotective actions of taurine, such accumulation of taurine might constitute a compensatory mechanism that attempts to prevent neurodegeneration.

nutrients-14-01292-g003

Taurine release is mainly mediated by volume-regulated anion channels (VRAC) that are activated by hypo-osmotic conditions and electrical activity. They can be stimulated via glutamate metabotropic (mGluR) and ionotropic receptors (mainly NMDA and AMPA), adenosine A1 receptors (A1R), and metabotropic ATP receptors (P2Y).

Taurine mediates its neuromodulatory effects by binding to GABAA, GABAB, and glycine receptors. While taurine binding to GABAA and GABAB is weaker than to GABA, taurine is a rather potent ligand of the glycine receptor. Reuptake of taurine occurs via taurine transporter TauT.

Cytoprotective actions of taurine contribute to brain health improvements in subjects with obesity and diabetes through various mechanisms that improve neuronal function, such as:

  • Modulating inhibitory neurotransmission, which promotes an excitatory–inhibitory balance;
  • Stimulating antioxidant systems; and
  • Stabilizing mitochondria energy production and Ca2+ homeostasis.”

https://www.mdpi.com/2072-6643/14/6/1292/htm “Taurine Supplementation as a Neuroprotective Strategy upon Brain Dysfunction in Metabolic Syndrome and Diabetes”


A second review focused on taurine’s secondary bile acids produced by gut microbiota:

“Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. Hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases.

Biliary acids may influence each of the following three mechanisms through which interactions within the brain-gut-microbiota axis take place: neurological, immunological, and neuroendocrine. These microbial metabolites can act as direct neurotransmitters or neuromodulators, serving as key modulators of the brain-gut interactions.

The gut microbial community, through their capacity to produce bile acid metabolites distinct from the liver, can be thought of as an endocrine organ with potential to alter host physiology, perhaps to their own favour. Hydrophilic bile acids, currently regarded as important hormones, exert modulatory effects on gut microbiota composition to produce secondary bile acids which seem to bind a number of receptors with a higher affinity than primary biliary acids, expressed on many different cells.

40035_2022_307_Fig1_HTML

TUDCA regulates expression of genes involved in cell cycle regulation and apoptotic pathways, promoting neuronal survival. TUDCA:

  • Improves protein folding capacity through its chaperoning activity, in turn reducing protein aggregation and deposition;
  • Reduces reactive oxygen species production, leading to protection against mitochondrial dysfunction;
  • Ameliorates endoplasmic reticulum stress; and
  • Inhibits expression of pro-inflammatory cytokines, exerting an anti-neuroinflammatory effect.

Although Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and cerebral ischemia have different disease progressions, they share similar pathways which can be targeted by TUDCA. This makes this bile acid a potentially strong therapeutic option to be tested in human diseases. Clinical evidence collected so far has reported comprehensive data on ALS only.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166453/ “Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases”

Eat broccoli sprouts for depression, Part 2

Here are three papers that cited last year’s Part 1. First is a 2021 rodent study investigating a microRNA’s pro-depressive effects:

“Depressive rat models were established via chronic unpredicted mild stress (CUMS) treatment. Cognitive function of rats was assessed by a series of behavioral tests.

Nrf2 CUMS

Nrf2 was weakly expressed in CUMS-treated rats, whereas Nrf2 upregulation alleviated cognitive dysfunction and brain inflammatory injury.

Nrf2 inhibited miR-17-5p expression via binding to the miR-17-5p promoter. miR-17-5p was also found to limit wolfram syndrome 1 (Wfs1) transcription.

We found that Nrf2 inhibited miR-17-5p expression and promoted Wfs1 transcription, thereby alleviating cognitive dysfunction and inflammatory injury in rats with depression-like behaviors. We didn’t investigate the role of Nrf2 in other depression models (chronic social stress model and chronic restraint stress model) and important brain regions other than hippocampus, such as prefrontal cortex and nucleus accumbens. Accordingly, other depression models and brain regions need to be designed and explored to further validate the role of Nrf2 in depression in future studies.”

https://link.springer.com/article/10.1007/s10753-021-01554-4 “Nrf2 Alleviates Cognitive Dysfunction and Brain Inflammatory Injury via Mediating Wfs1 in Rats with Depression‑Like Behaviors” (not freely available)

This study demonstrated that activating the Nrf2 pathway inhibited brain inflammation, cognitive dysfunction, and depression. Would modulating one microRNA and one gene in vivo without Nrf2 activation achieve similar results?


A 2021 review focused on the immune system’s role in depression:

“Major depressive disorder is one of the most common psychiatric illnesses. The mean age of patients with this disorder is 30.4 years, and the prevalence is twice higher in women than in men.

Activation of inflammatory pathways in the brain is considered to be an important producer of excitotoxicity and oxidative stress inducer that contributes to neuronal damage seen in the disorder. This activation is mainly due to pro-inflammatory cytokines activating the tryptophan-kynurenine (KP) pathway in microglial cells and astrocytes.

Elevated levels of cortisol exert an inhibitory feedback mechanism on its receptors in the hippocampus and hypothalamus, stopping stimulation of these structures to restore balance. When this balance is disrupted, hypercortisolemia directly stimulates extrahepatic enzyme 2,3-indolimine dioxygenase (IDO) located in various tissues (intestine, placenta, liver, and brain) and immune system macrophages and dendritic cells.

Elevation of IDO activities causes metabolism of 99% of available tryptophan in the KP pathway, substantially reducing serotonin synthesis, and producing reactive oxygen species and nitrogen radicals. The excitotoxicity generated produces tissue lesions, and activates the inflammatory response.”

https://academic.oup.com/ijnp/article/25/1/46/6415265 “Inflammatory Process and Immune System in Major Depressive Disorder”

This review highlighted that stress via cortisol and IDO may affect the brain and other parts of the body.


A 2022 review elaborated on Part 1’s findings of MeCP2 as a BDNF inhibitor:

“Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator that is highly abundant in the brain. It binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity.

Ability to cope with stressors relies upon activation of the hypothalamic–pituitary–adrenal (HPA) axis. MeCP2 has been shown to contribute to early life stress-dependent epigenetic programming of genes that enhance HPA-axis activity.

We describe known functions of MeCP2 as an epigenetic regulator, and provide evidence for its role in modulating synaptic plasticity via transcriptional regulation of BDNF or other proteins involved in synaptogenesis and synaptic strength like reelin. We conclude that MeCP2 is a promising target for development of novel, more efficacious therapeutics for treatment of stress-related disorders such as depression.”

https://www.mdpi.com/2073-4409/11/4/748/htm “The Role of MeCP2 in Regulating Synaptic Plasticity in the Context of Stress and Depression”


Osprey lunch

PXL_20220221_192924474

Gut microbiota’s positive epigenetic effects

Three papers with the first a 2021 review:

“Gut microbiota along with their metabolites are involved in health and disease through multiple epigenetic mechanisms including:

  • Affecting transporter activities, e.g. DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs);
  • Providing methyl donors to participate in DNA methylation and histone modifications; and
  • miRNAs that can lead to gene transcriptional modifications.

ijms-22-06933-g003

These mechanisms can participate in a variety of biological processes such as:

  • Maturation of intestinal epithelial cells (IECs);
  • Maintenance of intestinal homeostasis;
  • Inflammatory response;
  • Development of metabolic disorders; and
  • Prevention of colon cancer.”

https://www.mdpi.com/1422-0067/22/13/6933/htm “Dissecting the Interplay Mechanism between Epigenetics and Gut Microbiota: Health Maintenance and Disease Prevention”


A second 2022 review added subjects such as crotonate (aka unsaturated butyrate):

“Studies are carving out potential roles for additional histone modifications, such as crotonylation and ethylation, in facilitating crosstalk between microbiota and host. Lysine crotonylation is a relatively less studied histone modification that is often enriched at active promoters and enhancers in mammalian cells.

While addition or removal of crotonyl motifs can be catalyzed by specialized histone crotonyltransferases and decrotonylases, HATs and HDACs have also been reported to exhibit histone crotonyl-modifying activity. Microbiota stimulate multiple types of histone modifications and regulate activity of histone-modifying enzymes to calibrate local and extra-intestinal chromatin landscapes.”

https://www.tandfonline.com/doi/full/10.1080/19490976.2021.2022407 “Epigenetic regulation by gut microbiota”


A third 2021 review added subjects such as broccoli sprout compounds’ epigenetic effects:

“Glucosinolates are converted into isothiocyanates (ITCs) by bacteria that regulate host epigenetics. Levels of ITCs produced following broccoli consumption are highly dependent on the functional capacity of individual microbiomes, as much interindividual variability exists in gut microbiota composition and function in humans.

Sulforaphane inhibits HDAC activity both in vitro and in vivo, and protects against tumor development. Microbial-mediated production of ITCs represents a strong diet-microbe interaction that has a direct impact on host epigenome and health.”

https://www.sciencedirect.com/science/article/pii/S0955286321000516 “The interplay between diet, gut microbes, and host epigenetics in health and disease”


Clearing the channel

PXL_20220118_203446833

Defend yourself with taurine

This densely packed 2021 review subject was taurine:

“Taurine (Tau), a sulphur-containing non-proteinogenic β-amino acid, has a special place as an important natural modulator of antioxidant defence networks:

  • Direct antioxidant effect of Tau due to scavenging free radicals is limited, and could be expected only in a few tissues (heart and eye) with comparatively high concentrations.
  • Maintaining optimal Tau status of mitochondria controls free radical production.
  • Indirect antioxidant activities of Tau due to modulating transcription factors leading to upregulation of the antioxidant defence network are likely to be major molecular mechanisms of Tau’s antioxidant and anti-inflammatory activities.
  • A range of toxicological models clearly show protective antioxidant-related effects of Tau.”

antioxidants-10-01876-g001-550

https://www.mdpi.com/2076-3921/10/12/1876/htm “Taurine as a Natural Antioxidant: From Direct Antioxidant Effects to Protective Action in Various Toxicological Models”


PXL_20211226_120547077

Dementia blood factors

This 2021 human study performed blood metabolite analyses:

“Dementia is a collective term to describe various symptoms of cognitive impairment in a condition in which intelligence is irreversibly diminished due to acquired organic disorders of the brain, characterized by deterioration of memory, thinking, behavior, and the ability to perform daily activities.

In this study, we conducted nontargeted, comprehensive analysis of blood metabolites in dementia patients. Effort expended in this ‘no assumptions’ approach is often recompensed by identification of diagnostic compounds overlooked by targeted analysis.

The great variability of data in Figure 1 reflects genuine individual variation in metabolites, which were accurately detected by our metabolomic analysis. These data demonstrate that compounds having small to large individual variability are implicated in dementia.

dementia blood factors

7 group A compounds – plasma-enriched dementia factors – increased in dementia patients and might have a negative toxic impact on central nervous system (CNS) functions by themselves or their degradation products.

26 group B to E metabolites may be beneficial for the CNS, as their quantity all declined in dementia patients:

  • Red blood cell (RBC)-enriched group B metabolites all containing the trimethyl-ammonium ion may protect the CNS through their antioxidative and other activity.
  • Group C compounds, also RBC-enriched, have cellular functions implicated in energy, redox, and so forth, and may be important for maintaining CNS brain functions.
  • Group D’s 12 plasma compounds (amino acids, nucleosides, choline, and carnitine) – half of which had been reported as Alzheimer’s disease (AD)-related markers – may underpin actions of other metabolites for supply and degradation. Consistency of group D plasma metabolites as dementia markers but not group B and C RBC metabolites validated the method of searching dementia markers that we employed in the present study.
  • Group E compounds, caffeine and and its derivative dimethyl-xanthine, declined greatly in dementia subjects. Caffeine is an antagonist of adenosine, consistent with the present finding that adenosine belongs to group A compounds.

Twelve [groups B + C] of these 33 compounds are RBC-enriched, which has been scarcely reported. The majority of metabolites enriched in RBCs were not identified in previous studies.

Nine compounds possessing trimethylated ammonium ions are amphipathic compounds (with both hydrophilic and lipophilic properties) and form the basis of lipid polymorphism. All of them showed a sharp decline in abundance in dementia subjects.

amphipathic compounds

These amphipathic compounds may have similar roles, forming a higher-ordered, assembled structure. They might act as major neuroprotectants or antioxidants in the brain, and their levels are sensitive to both antioxidants and ROS.

We speculate the 7 group A compounds pathologically enhance or lead to severe dementia such as AD. This presumed dementia deterioration by group A factors is opposed if group B to E metabolites are sufficiently supplied.

However, group A markers were not found in frail subjects. If the change in group A is causal for dementia, then a cognitive cause in frailty may be distinct from that of dementia.”

https://www.pnas.org/content/118/37/e2022857118 “Whole-blood metabolomics of dementia patients reveal classes of disease-linked metabolites”


Dementia subjects (ages 75-88) lived in an Okinawa hospital. Healthy elderly (ages 67-80) and young (ages 28-34) subjects lived in a neighboring village. Of the 24 subjects, 3 dementia and 1 healthy elderly were below a 18.5 to <25 BMI range, and none were above.

Get neuroprotectants working for you. Previous relevant curations included:

Natural products vs. neurodegenerative diseases

I was recently asked about taking rapamycin for its effects on mTOR. I replied that diet could do the same thing. Here’s a 2021 review outlining such effects:

“As common, progressive, and chronic causes of disability and death, neurodegenerative diseases (NDDs) significantly threaten human health, while no effective treatment is available. Recent studies have revealed the role of phosphoinositide 3-kinase (PI3K)/Akt (Protein kinase B)/mammalian target of rapamycin (mTOR) in some diseases and natural products with therapeutic potentials.

Growing evidence highlights the dysregulated PI3K/Akt/mTOR pathway and interconnected mediators in pathogenesis of NDDs. Side effects and drug-resistance of conventional neuroprotective agents urge the need for providing alternative therapies.

1-s2.0-S0944711321002075-ga1_lrg

Polyphenols, alkaloids, carotenoids, and terpenoids have shown to be capable of a great modulation of PI3K/Akt/mTOR in NDDs. Natural products potentially target various important oxidative/inflammatory/apoptotic/autophagic molecules/mediators, such as Bax, Bcl-2, p53, caspase-3, caspase-9, NF-κB, TNF-α, GSH, SOD, MAPK, GSK-3β, Nrf2/HO-1, JAK/STAT, CREB/BDNF, ERK1/2, and LC3 towards neuroprotection.

This is the first systematic and comprehensive review with a simultaneous focus on the critical role of PI3K/Akt/mTOR in NDDs and associated targeting by natural products.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711321002075 “Natural products attenuate PI3K/Akt/mTOR signaling pathway: A promising strategy in regulating neurodegeneration” (not freely available) Thanks to Dr. Sajad Fakhri for providing a copy.


Natural products mentioned in this review that I eat in everyday foods are listed below. The most effective ones are broccoli and red cabbage sprouts, and oats and oat sprouts:

  • Artichokes – luteolin;
  • Blackberries – anthocyanins;
  • Blueberries – anthocyanins, gallic acid, pterostilbene;
  • Broccoli and red cabbage sprouts – anthocyanins, kaempferol, luteolin, quercetin, sulforaphane;
  • Carrots – carotenoids;
  • Celery – apigenin, luteolin;
  • Green tea – epigallocatechin gallate;
  • Oats and oat sprouts – avenanthramides;
  • Strawberries – anthocyanins, fisetin;
  • Tomatoes – fisetin.

Four humpback whales

PXL_20210914_170732350_exported_43137

Screenshot_20210914-121800

Blood pressure and pain

A trio of papers, with the second and third citing a 2013 review:

“The relationship between pain and hypertension is potentially of great pathophysiological and clinical interest, but is poorly understood. Perception of acute pain initially plays an adaptive role, which results in prevention of tissue damage.

The consequence of ascending nociception is recruitment of segmental spinal reflexes through physiological neuronal connections:

  • In proportion to magnitude and duration of the stimulus, these spinal reflexes cause sympathetic nervous system activation, which increases peripheral resistances, heart rate, and stroke volume; and
  • The response also involves the neuroendocrine system, in particular, the hypothalamic-pituitary-adrenal axis, in addition to further activation of the sympathetic system by adrenal glands.

Persistent pain tends to become chronic and to increase BP values. After a long time, dysfunction of release of endogenous opioids results in a reduction of their analgesic effect. A vicious circle is established, where further pain leads to a reduction in pain tolerance, associated with decreased analgesia mediated by baroreceptors, in a kind of process of exhaustion.”

https://onlinelibrary.wiley.com/doi/epdf/10.1111/jch.12145 “The Relationship Between Blood Pressure and Pain”


A second paper was a 2021 human experimental pain study:

“We investigated the effectiveness of physiological signals for automatic pain intensity estimation that can either substitute for, or complement patients’ self-reported information. Results indicate that for both subject-independent and subject-dependent scenarios, electrodermal activity (EDA) – which is also referred to as skin conductance (SC) or galvanic skin response – was the best signal for pain intensity estimation.

EDA gave mean absolute error (MAE) = 0.93 using only 3 time-series features:

  1. Time intervals between successive extreme events above the mean;
  2. Time intervals between successive extreme events below the mean; and
  3. Exponential fit to successive distances in 2-dimensional embedding space.

Although we obtained good results using 22 EDA features, we further explored to see if we could reach similar or better results with fewer EDA features. This plot highlights that by considering only the top 3 features, we obtained the same level of performance given by all 22 features together.

journal.pone.0254108.g002

This is the first study that achieved less than 1-unit error for continuous pain intensity estimation using only one physiological sensor’s 3 time-series feature, and a Support Vector Regression machine learning model. Considering that this is an encouraging result, we can estimate objective pain using only the EDA sensor, which needs neither a complex setup nor a complex computationally intense machine learning algorithm.

This study paves the way for developing a smart pain measurement wearable device that can change the quality of pain management significantly.”

https://doi.org/10.1371/journal.pone.0254108 “Exploration of physiological sensors, features, and machine learning models for pain intensity estimation”


A third paper was a 2020 human rotator cuff surgery study:

“Results of our study demonstrated that:

  • Pain during the early postoperative period;
  • Time until occurrence of a retear; and
  • Existence of hypertension

were correlated with severity of pain in patients with a retorn rotator cuff.

Pain was selected as the sole outcome parameter of this study because:

  • Pain is an important factor that compels patients to seek treatment for rotator cuff tears, along with functional disability;
  • Pain and subjective functional deficits are important factors that influence a surgeon’s decision to continue with treatment in cases of retearing; and
  • Analyzing pain severity can be a good way to determine patients’ overall satisfaction after rotator cuff repair.

However, pain is not always correlated with disease severity or tear size and vice versa. A lack of pain does not necessarily depend on integrity of the repaired tendon or constitute a good prognosis. In fact, patients with partial-thickness rotator cuff tears showed more pain than did those with full-thickness tears.

Existence of hypertension had a proportional relationship with pain at 12 months postoperatively in patients with retears. This can be interpreted as a suggestion that pain in patients with retears is not acute, but rather chronic, and may be connected to pain in the early postoperative period at 3 months. However, results of this study cannot explain benefits of controlling hypertension in alleviating pain in patients with retears.”

https://journals.sagepub.com/doi/10.1177/2325967120947414 “Factors Related to Pain in Patients With Retorn Rotator Cuffs: Early Postoperative Pain Predicts Pain at 12 Months Postoperatively”


PXL_20210722_100353787

Ride the waves of gene expression with betaine

This 2021 cell study investigated a dietary supplement’s role in preventing nerve disease:

“A loss of epigenetic control has been implicated in development of neurodegenerative diseases. Previous studies have implicated aberrant DNA and histone methylation in multiple sclerosis (MS) disease pathogenesis.

We have previously reported that methyl donor betaine is depleted in MS and is linked to changes in histone H3 trimethylation (H3K4me3) in neurons. We have also shown that betaine increases histone methyltransferase activity by activating chromatin bound betaine homocysteine S-methyltransferase (BHMT).

A hallmark of MS is the death of oligodendrocytes, the cells responsible for wrapping axons in myelin in the central nervous system and maintaining a healthy sheath. In demyelinating diseases like MS, oligodendrocyte progenitor cells (OPCs) fail to differentiate and make more myelin, resulting in sclerotic lesions.

Promoting differentiation of OPCs and generation of myelin is of great interest as a novel MS therapy. Waves of gene regulation (repression and activation) need to occur to promote myelination.

This BHMT-betaine methylation pathway ensures availability of S-adenosylmethionine (SAM) for a variety of DNA and histone methylation processes. OPC survival and differentiation are dependent upon DNA and histone methylation, and both processes require SAM.

journal.pone.0250486.g001

BHMT uses betaine to remethylate homocysteine to methionine. Betaine can be taken in through the diet or synthesized through the oxidation of choline in mitochondria.

We demonstrated that oligodendrocyte gene expression can be modulated by betaine supplementation through the BHMT-betaine methylation pathway. Our study suggests that dietary betaine supplementation may prove to be a therapeutic agent for MS and other demyelinating disorders.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250486 “The BHMT-betaine methylation pathway epigenetically modulates oligodendrocyte maturation”


I started taking betaine 16 years ago. Didn’t know of these effects until reading this study.

Treating psychopathological symptoms will somehow resolve causes? had more on betaine (aka trimethyl glycine). Current dose is 1.5 grams twice daily.

The future of your brain is in your gut right now

A 2020 paper by the author of Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease:

“The gut and brain communicate bidirectionally via several pathways which include:

  1. Neural via the vagus nerve;
  2. Endocrine via the HPA axis;
  3. Neurotransmitters, some of which are synthesized by microbes;
  4. Immune via cytokines; and
  5. Metabolic via microbially generated short-chain fatty acids.

How does nature maintain the gut-microbiome-brain axis? Mechanisms to maintain homeostasis of intestinal epithelial cells and their underlying cells are a key consideration.

The symbiotic relationship that exists between microbiota and the human host is evident when considering nutrient requirements of each. The host provides food for microbes, which consume that food to produce metabolites necessary for health of the host.

Consider function of the human nervous system, not in isolation but in integration with the gastrointestinal ecosystem of the host, in expectation of a favorable impact on human health and behavior.”

https://www.sciencedirect.com/science/article/pii/B9780128205938000148 “Chapter 14 – The gut microbiome: its role in brain health” (not freely available)


Always more questions:

  1. What did you put into your gut today?
  2. What type of internal environment did it support?
  3. What “favorable impact on human health and behavior” do you expect from today’s intake?
  4. How will you feel?
  5. Will you let evidence guide feeding your gut environment?

See Harnessing endogenous defenses with broccoli sprouts for further elaboration. See Switch on your Nrf2 signaling pathway for an interview with these papers’ author.

Eat oats today!

This 2020 food chemistry review provided phenolic-compound reasons to eat oats:

“Phenolamides result from the conjugation of hydroxycinnamic acids with amines. These products contain a variety of metabolic, chemical, and functional capabilities due to the large number of possible combinations among the parent compounds.

Of the currently known phenolamides, the most common are avenanthramides (AVAs), which are unique in oats. AVAs possess anti-inflammatory, anti-itch, anti-atherosclerosis, antioxidant, anti-cancer, anti-obesity, anti-fungal, anti-microbial, and neuroprotective properties.

Twenty-nine C-type AVAs have been identified in oats, and twenty-six A-type AVAs.

  • C-type AVAs in commercially available oat products range from 36.49-61.77 mg/kg (fresh weight).
  • A-type AVAs represent approximately 22.5% of total AVA levels in regular oats and 24.7-33.0% in commercial sprouted oats.

Steeping raw groats increased AVA concentrations.”

These reviews were referenced:

“Since publication of these two reviews, a few new studies reported AVAs’ beneficial health effects, mainly related to their anti-inflammatory and anti-cancer activities. AVAs can:

  • Significantly decrease IL-6, IL-8, and MCP-1 in endothelial cells;
  • Inhibit IL-1β- and TNF-α-induced NF-κB activation; as well as
  • Expression of adhesion molecules; and
  • Adhesion of monocytes to endothelial cell monolayer.

In 2020, the first evaluation of anti-inflammation effects of A-type AVAs was published from our own group. Fifteen A-type AVAs from commercial sprouted oat products interacted with lipopolysaccharide-induced nitric oxide production and iNOS expression.

Colloidal oatmeal’s natural components, AVAs, help to restore and maintain skin barrier function. AVAs are safe, well tolerated, and can be effective as adjuvant treatment in atopic dermatitis.

In one mouse model, a C-type AVA was able to mitigate many adverse effects of Alzheimer’s Disease. It restored hippocampal long-term potentiation and synaptic function, enhanced memory function, suppressed pro-inflammatory cytokines TNF-α and IL-6 levels, reduced caspase-3 levels, and increased pS9GSK-3β and IL-10 levels.

AVAs downregulated expression of hTERT and MDR1, pro-survival genes for cancer cells, and COX-2 mRNA and PGE2 levels, known pro-inflammatory markers. AVAs induced apoptosis by activating caspases 8, 3, and 2.”

https://pubs.acs.org/doi/10.1021/acs.jafc.0c02605 “The Chemistry and Health Benefits of Dietary Phenolamides” (not freely available)


Hadn’t thought about sprouting oats before this paper.

Clearing out the 2020 queue of interesting papers

I’ve partially read these 39 studies and reviews, but haven’t taken time to curate them.

Early Life

  1. Intergenerational Transmission of Cortical Sulcal Patterns from Mothers to their Children (not freely available)
  2. Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats
  3. Maternal Diabetes Induces Immune Dysfunction in Autistic Offspring Through Oxidative Stress in Hematopoietic Stem Cells
  4. Maternal prenatal depression and epigenetic age deceleration: testing potentially confounding effects of prenatal stress and SSRI use
  5. Maternal trauma and fear history predict BDNF methylation and gene expression in newborns
  6. Adverse childhood experiences, posttraumatic stress, and FKBP5 methylation patterns in postpartum women and their newborn infants (not freely available)
  7. Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: a randomized, double‐blind, controlled feeding study
  8. Preterm birth is associated with epigenetic programming of transgenerational hypertension in mice
  9. Epigenetic mechanisms activated by childhood adversity (not freely available)

Epigenetic clocks

  1. GrimAge outperforms other epigenetic clocks in the prediction of age-related clinical phenotypes and all-cause mortality (not freely available)
  2. Epigenetic age is a cell‐intrinsic property in transplanted human hematopoietic cells
  3. An epigenetic clock for human skeletal muscle
  4. Immune epigenetic age in pregnancy and 1 year after birth: Associations with weight change (not freely available)
  5. Vasomotor Symptoms and Accelerated Epigenetic Aging in the Women’s Health Initiative (WHI) (not freely available)
  6. Estimating breast tissue-specific DNA methylation age using next-generation sequencing data

Epigenetics

  1. The Intersection of Epigenetics and Metabolism in Trained Immunity (not freely available)
  2. Leptin regulates exon-specific transcription of the Bdnf gene via epigenetic modifications mediated by an AKT/p300 HAT cascade
  3. Transcriptional Regulation of Inflammasomes
  4. Adipose-derived mesenchymal stem cells protect against CMS-induced depression-like behaviors in mice via regulating the Nrf2/HO-1 and TLR4/NF-κB signaling pathways
  5. Serotonin Modulates AhR Activation by Interfering with CYP1A1-Mediated Clearance of AhR Ligands
  6. Repeated stress exposure in mid-adolescence attenuates behavioral, noradrenergic, and epigenetic effects of trauma-like stress in early adult male rats
  7. Double-edged sword: The evolutionary consequences of the epigenetic silencing of transposable elements
  8. Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation
  9. Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights
  10. Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein
  11. Chronic Mild Stress Modified Epigenetic Mechanisms Leading to Accelerated Senescence and Impaired Cognitive Performance in Mice
  12. FKBP5-associated miRNA signature as a putative biomarker for PTSD in recently traumatized individuals
  13. Metabolic and epigenetic regulation of T-cell exhaustion (not freely available)

Aging

  1. Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches
  2. Epigenetic regulation of bone remodeling by natural compounds
  3. Microglial Corpse Clearance: Lessons From Macrophages
  4. Plasma proteomic biomarker signature of age predicts health and life span
  5. Ancestral stress programs sex-specific biological aging trajectories and non-communicable disease risk

Broccoli sprouts

  1. Dietary Indole-3-Carbinol Alleviated Spleen Enlargement, Enhanced IgG Response in C3H/HeN Mice Infected with Citrobacter rodentium
  2. Effects of caffeic acid on epigenetics in the brain of rats with chronic unpredictable mild stress
  3. Effects of sulforaphane in the central nervous system
  4. Thiol antioxidant thioredoxin reductase: A prospective biochemical crossroads between anticancer and antiparasitic treatments of the modern era (not freely available)
  5. Quantification of dicarbonyl compounds in commonly consumed foods and drinks; presentation of a food composition database for dicarbonyls (not freely available)
  6. Sulforaphane Reverses the Amyloid-β Oligomers Induced Depressive-Like Behavior (not freely available)

Dietary contexts matter

Two papers illustrated how actions of food compounds are affected by their contexts. The first was a 2020 UCLA rodent study:

“Long-chain polyunsaturated fatty acids (PUFAs), particularly omega-3 (n-3) PUFAs, have been indicated to play important roles in various aspects of human health. Controversies are observed in epidemiological and experimental studies regarding the benefits or lack of benefits of n-3 PUFAs.

Dietary docosahexaenoic acid (DHA; 22:6 n-3) supplementation improved select metabolic traits and brain function, and induced transcriptomic and epigenetic alterations in hypothalamic and hippocampal tissues in both context-independent and context-specific manners:

  • In terms of serum triglyceride, glycemic phenotypes, insulin resistance index, and memory retention, DHA did not affect these phenotypes significantly when examined on the chow diet background, but significantly improved these phenotypes in fructose-treated animals.
  • Genes and pathways related with tissue structure were affected by DHA regardless of the dietary context, although the direction of changes are not necessarily the same between contexts. These pathways may represent the core functions of DHA in maintaining cell membrane function and cell signaling.
  • DHA affected the mTOR signaling pathway in hippocampus. In the hypothalamus, altered pathways were more related to innate immunity, such as cytokine-cytokine receptors, NF-κB signaling pathway, and Toll-like receptor signaling pathway.

DHA exhibits differential influence on epigenetic loci, genes, pathways, and metabolic and cognitive phenotypes under different dietary contexts.”

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202000788 “Multi‐tissue Multi‐omics Nutrigenomics Indicates Context‐specific Effects of DHA on Rat Brain” (not freely available)


A human equivalent age period of the subjects was 12 to 20 years old. If these researchers want to make their study outstanding, they’ll contact their UCLA colleague Dr. Steven Horvath, and apply his new human-rat relative biological age epigenetic clock per A rejuvenation therapy and sulforaphane.

The second paper was a 2016 review Interactions between phytochemicals from fruits and vegetables: Effects on bioactivities and bioavailability (not freely available):

“The biological activities of food phytochemicals depend upon their bioaccessibility and bioavailability which can be affected by the presence of other food components including other bioactive constituents. For instance, α-tocopherol mixed with a flavonol (kaempferol or myricetin) is more effective in inhibiting lipid oxidation induced by free radicals than each component alone.

Interactions of phytochemicals may enhance or reduce the bioavailability of a given compound, depending on the facilitation/competition for cellular uptake and transportation. For example, β-carotene increases the bioavailability of lycopene in human plasma, and quercetin-3-glucoside reduces the absorption of anthocyanins.

Combinations of food extracts containing hydrophilic antioxidants and lipophilic antioxidants showed very high synergistic effects on free radical scavenging activities. A number of phytochemical mixtures and food combinations provide synergistic effects on inhibiting inflammation.

More research should be conducted to understand mechanisms of bioavailability interference considering physiological concentrations, food matrices, and food processing.”


Each of us can set appropriate contexts for our food consumption. Broccoli sprout synergies covered how I take supplements and broccoli sprouts together an hour or two before meals to keep meal contents from lowering sulforaphane bioavailability.

Combinations of my 19 supplements and broccoli sprouts are too many (616,645) for complete analyses. Just pairwise comparisons like the second paper’s example below would be 190 combinations.

binary isobologram

Contexts for each combination’s synergistic, antagonistic, or additive activities may also be influenced by other combinations’ results.

My consumption of flax oil (alpha linolenic acid C18:3) probably has effects similar to DHA since it’s an omega-3 PUFA and I take it with food. The first study’s human equivalent DHA dose was 100mg/kg, with its citation for clinical trials stating “1–9 g/day (0.45–4% of calories) n-3 PUFA.”

A 2020 review Functional Ingredients From Brassicaceae Species: Overview and Perspectives had perspectives such as:

“In many circumstances, the isolated bioactive is not as bioavailable or metabolically active as in the natural food matrix.”

It discussed categories but not combinations of phenolics, carotenoids, phytoalexins, terpenes, phytosteroids, and tocopherols, along with more well-known broccoli compounds.


Diving for breakfast

Treating psychopathological symptoms will somehow resolve causes?

This 2020 Swiss review subject was potential glutathione therapies for stress:

“We examine available data supporting a role for GSH levels and antioxidant function in the brain in relation to anxiety and stress-related psychopathologies. Several promising compounds could raise GSH levels in the brain by either increasing availability of its precursors or expression of GSH-regulating enzymes through activation of Nrf2.

GSH is the main cellular antioxidant found in all mammalian tissues. In the brain, GSH homeostasis has an additional level of complexity in that expression of GSH and GSH-related enzymes are not evenly distributed across all cell types, requiring coordination between neurons and astrocytes to neutralize oxidative insults.

Increased energy demand in situations of chronic stress leads to mitochondrial ROS overproduction, oxidative damage and exhaustion of GSH pools in the brain.

Several compounds can function as precursors of GSH by acting as cysteine (Cys) donors such as taurine or glutamate (Glu) donors such as glutamine (Gln). Other compounds stimulate synthesis and recycling of GSH through activation of the Nrf2 pathway including sulforaphane and melatonin. Compounds such as acetyl-L-carnitine can increase GSH levels.”

https://www.sciencedirect.com/science/article/abs/pii/S0149763419311133 “Therapeutic potential of glutathione-enhancers in stress-related psychopathologies” (not freely available)


Many animal studies of “stress-related psychopathologies” were cited without noting applicability to humans. These reviewers instead had curious none-of-this-means-anything disclaimers like:

“Comparisons between studies investigating brain disorders of such different nature such as psychiatric disorders or neurodegenerative diseases, or even between brain or non-brain related disorders should be made with caution.”

Regardless, this paper had informative sections for my 27th week of eating broccoli sprouts every day.

1. I forgot to mention in Broccoli sprout synergies that I’ve taken 500 mg of trimethyl glycine (aka betaine) twice a day for over 15 years. Section 3.1.2 highlighted amino acid glycine:

“Endogenous synthesis is insufficient to meet metabolic demands for most mammals (including humans) and additional glycine must be obtained from diet. While most research has focused on increasing cysteine levels in the brain in order to drive GSH synthesis, glycine supplementation alone or in combination with cysteine-enhancing compounds are gaining attention for their ability to enhance GSH.”

2. Taurine dropped off my supplement regimen last year after taking 500 mg twice a day for years. It’s back on now after reading Section 3.1.3:

“Most studies that reported enhanced GSH in the brain following taurine treatment were performed under a chronic regimen and used in age-related disease models.

Such positive effects of taurine on GSH levels may be explained by the fact that cysteine is the essential precursor to both metabolites, whereby taurine supplementation may drive metabolism of cysteine towards GSH synthesis.”

3. A study in Upgrade your brain’s switchboard with broccoli sprouts was cited for its potential:

“Thalamic GSH values significantly correlated with blood GSH levels, suggesting that peripheral GSH levels may be a marker of brain GSH content. Studies point to the capacity of sulforaphane to function both as a prophylactic against stress-induced behavioral changes and as a positive modulator in healthy animals.”


Sunrise minus 5 minutes

Unraveling oxytocin – is it nature’s medicine?

This 2020 review attempted to consolidate thousands of research papers on oxytocin:

“Chemical properties of oxytocin make this molecule difficult to work with and to measure. Effects of oxytocin are context-dependent, sexually dimorphic, and altered by experience. Its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug.

Widely used medical interventions i.e.:

  • Exogenous oxytocin, such as Pitocin given to facilitate labor;
  • Opioid medications that block the oxytocin system; or
  • Cesarean sections that alter exposure to endogenous oxytocin

have lasting consequences for the offspring and/or mother.

Such exposures hold the potential to have epigenetic effects on the oxytocin systems, including changes in DNA methylation. These changes in turn would have lasting effects on the expression of receptors for oxytocin, leaving individuals differentially able to respond to oxytocin and also possibly to the effects of vasopressin.

Regions with especially high levels of OXTR [oxytocin receptor gene] are:

  • Various parts of the amygdala;
  • Bed nucleus of the stria terminalis;
  • Nucleus accumbens;
  • Brainstem source nuclei for the autonomic nervous system;
  • Systems that regulate the HPA axis; as well as
  • Brainstem tissues involved in pain and social attention.

Oxytocin protects neural cells against hypoxic-ischemic conditions by:

  • Preserving mitochondrial function;
  • Reducing oxidative stress; and
  • Decreasing a chromatin protein that is released during inflammation

which can activate microglia through the receptor for advanced glycation end products (RAGE). RAGE acts as an oxytocin-binding protein facilitating the transport of oxytocin across the blood-brain barrier and through other tissues.

Directionality of this transport is 5–10 times higher from the blood to the brain, in comparison with brain to blood transport. Individual differences in RAGE could help to predict cellular access to oxytocin and might also facilitate access to oxytocin under conditions of stress or illness.

Oxytocin and vasopressin and their receptors are genetically variable, epigenetically regulated, and sensitive to stressors and diet across the lifespan. As one example, salt releases vasopressin and also oxytocin.

Nicotine is a potent regulator of vasopressin. Smoking, including prenatal exposure of a fetus, holds the potential to adjust this system with effects that likely differ between males and females and that may be transgenerational.

Relative concentrations of endogenous oxytocin and vasopressin in plasma were associated with:

These studies support the usefulness of measurements of both oxytocin and vasopressin but leave many empirical questions unresolved.

The vast majority of oxytocin in biosamples evades detection using conventional approaches to measurement.”

https://pharmrev.aspetjournals.org/content/pharmrev/72/4/829.full.pdf “Is Oxytocin Nature’s Medicine?”


I appreciated efforts to extract worthwhile oxytocin research from countless poorly performed studies, research that wasted resources, and research that actually detracted from science.

I was disappointed that at least one of the reviewers didn’t take this review as an opportunity to confess their previous wastes like three flimsy studies discussed in Using oxytocin receptor gene methylation to pursue an agenda.

Frank interpretations of one’s own study findings to acknowledge limitations is one way researchers can address items upfront that will be questioned anyway. Such analyses also indicate a goal to advance science.

Although these reviewers didn’t provide concrete answers to many questions, they highlighted promising research areas, such as:

  • Improved approaches to oxytocin measurements;
  • Prenatal epigenetic experience associations with oxytocin and OXTR; and
  • Possible transgenerational transmission of these prenatal epigenetic experiences.

Eat broccoli sprouts for your hair!

A trio of papers, with the first a 2017 review exploring broccoli sprout compounds’ effects on head hair:

“Skin appendages, notably hair follicles (HFs), can be exposed to high levels of reactive oxygen species (ROS), which are generated through metabolic reactions occurring mostly in the mitochondria, peroxisomes and the endoplasmic reticulum as well as in the plasma membrane. Despite their involvement in redox stress and cellular damage, ROS also have key roles in physiological signalling processes, including but not limited to, control of stem cell quiescence / differentiation, regulation of innate and adaptive immune responses and importantly, normal HF development.

HFs are composed of a series of concentric keratinocyte layers with a central hair shaft, all of which are encapsulated by a mesenchymal connective tissue sheath. Within this structure is an area known as the ‘bulge’, housing a population of epithelial and melanocyte stem cells. The hair bulb, the lowermost portion of the HF, contains transient amplifying cells that produce the rapidly proliferating matrix keratinocytes that give rise to the various cell types of the inner root sheath and hair shaft itself.

Putative impact of NRF2 activation on protection against hair disorders:

  1. Accumulation of excess ROS within crucial HF compartments (i.e. bulb and bulge) can be induced by endogenous and exogenous stressors associated with androgenetic alopecia (AGA), alopecia areata (excessive mast cell degranulation), chemotherapy, UV exposure and even physiological processes such as melanogenesis.
  2. In the HFSCs [hair follicle stem cells] of the bulge, this can lead to reduced FOXP1 signaling, increased senescence and P21-mediated telogen retention, contributing the hair ageing.
  3. In the hair bulb, negative consequences of excessive ROS can include reduced matrix keratinocyte proliferation and Bcl-2 expression, coupled to increased p53 activity and apoptosis. This redox imbalance may also stimulate the dermal papilla-derived TGF-b1 release associated with AGA.
  4. NRF2 activation via SFN [sulforaphane] can induce the expression of numerous downstream targets, hence suggesting the potential to counteract excessive ROS and associated pathologies, for example via enhanced clearance of reactive species, detoxification, NADPH generation and GSH maintenance.
  5. In addition, NRF2 may down-regulate genes that would negatively impact on proliferation and stimulate apoptosis.
  6. Ultimately, the activation of NRF2 has the potential to protect against HF miniaturization, chemotherapy-induced apoptosis, HFSC aging and hair greying, through maintenance of normal redox homeostasis.

Whereas eumelanin (black) is involved in natural UV protection by reducing generation of free radicals, pheomelanin (red) can trigger generation of ROS. It would certainly be interesting to determine whether NRF2 activity is therefore higher in individuals with red as opposed to black hair, in order to mitigate any negative impact from higher ROS generation.

Modulation of NRF2 activity is an attractive approach for further study in the prevention of hair greying and HFSC ageing. The remarkable prospect for NRF2 activators in modulating other oxidative stress-linked disease states, strongly advocates for the development of NRF2 targeting as a novel strategy in modulating redox-associated disorders of the HF.”

https://onlinelibrary.wiley.com/doi/abs/10.1002/bies.201700029 “Oxidative stress management in the hair follicle: Could targeting NRF2 counter age‐related hair disorders and beyond?” (not freely available)


This review was cited in a 2020 Exploring the possibility of predicting human head hair greying from DNA using whole-exome and targeted NGS data study:

“This study aimed to assess the potential of genetic data to predict hair greying in a population of nearly 1000 individuals from Poland. Most of the prediction information was brought by age alone. Genetic variants explained < 10% of hair greying variation and the impact of particular SNPs on prediction accuracy was found to be small.

Study population included 673 males (67.4%) and 325 (32.6%) females. The mean age of the participants was 30.5 ± 8.8.

Hair greying was recorded in 14.3% of individuals aged 18–30 and the prevalence of grey hair was noted to be significantly higher in young males when comparing to young females (17.8 and 9.2%, respectively). The incidence of grey hair increased to 29.5% in the group of people aged 18–40 years and was 84.2% when people aged ≥40 years were considered.

Because pleiotropy is so common, it would be impossible to predict natural phenotypes avoiding genes involved in determination of pathological phenotypes. The penetrance of individual SNP variants is usually low and they altogether can only explain a small fraction of the predisposition to the disease.

Prediction of hair greying status solely based on genetic information is currently impossible.”


A 2020 review had a pertinent evaluation scheme:

“Geroprotectors are pharmacological agents that decrease the rate of aging and extend lifespan. We proposed a set of primary and secondary selection criteria for potential geroprotectors. Primary criteria:

  1. The life extension in experiments with wild type animal models. The geroprotector should prolong the life of the model beyond the intact maximum lifespan, protecting it from one or more mechanisms of aging.
  2. Improvement of molecular, cellular, and physiological biomarkers to a younger state or slow down the progression of age-related changes in humans.
  3. Most potential geroprotectors are preventive only when applied at relatively high concentrations. The lifespan-extending dose should be several orders of magnitude less than the toxic dose.
  4. Minimal side effects at the therapeutic dosage at chronic application.
  5. The potential benefit of taking a geroprotector may come after a long period. Potential geroprotectors should initially improve some parameters of health-related quality of life: physical, mental, emotional, or social functioning of the person.”

https://www.mdpi.com/2076-3921/9/6/529/htm “Terpenoids as Potential Geroprotectors”


IMG_20200822_064852