Nrf2 and circadian rhythm

This 2021 rodent study investigated aging’s effects:

“We investigated aging consequences on temporal patterns of antioxidant defenses, molecular clock machinery, and blood pressure.

We observed circadian rhythms of catalase (CAT) and glutathione peroxidase (GPx) mRNA expression, as well as ultradian rhythms of Nrf2 mRNA levels, in the hearts of young adult rats. We also found circadian oscillations of CAT and GPx enzymatic activities, reduced glutathione (GSH), and BMAL1 protein.

Aging abolished rhythms of CAT and GPx enzymatic activities, phase-shifted rhythm acrophases of GSH and BMAL1 protein levels, and turned circadian the ultradian oscillation of Nrf2 expression.

aging changes Nrf2 oscillation

Moreover, aging phase-shifted the circadian pattern of systolic blood pressure. In conclusion, aging modifies temporal organization of antioxidant defenses and blood pressure, probably as a consequence of disruption in the circadian rhythm of the clock’s transcriptional regulator, BMAL1, in heart.”

https://doi.org/10.1007/s10522-021-09938-7 “Aging disrupts the temporal organization of antioxidant defenses in the heart of male rats and phase shifts circadian rhythms of systolic blood pressure” (not freely available)


A human equivalent to this study’s 3-month-old young adult group is around 19 years. The older group’s 22-month age is roughly equivalent to a 68-year-old human.

Couldn’t say whether Nrf2 oscillations flattening out with age is specific to heart tissue, or is a more general trend. I’m pretty sure that humans have to make good things happen while aging, because bad things are pre-programmed.

I came across this study from a citation trail of a comment to Eat broccoli sprouts for your workouts. I didn’t curate the mentioned study because one of its coauthors tainted it by designing and supervising Problematic rodent sulforaphane studies.

How would you answer the comment’s question?


Repairs needed: The story of 2021

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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”


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Gut microbiota vs. disease risks

This 2021 review subject was risk relationships between diseases from the perspective of gut microbiota:

“There is a significant inverse relationship between the onset of Alzheimer’s disease/Parkinson’s disease (AD/PD) and cancer, but the mechanism is still unclear. Considering that intestinal flora can connect them, we briefly introduced the relationship among AD/PD, cancer, and intestinal flora, studied metabolites or components of the intestinal flora, and the role of intestinal barriers and intestinal hormones in AD/PD and cancer.

According to existing evidence:

  • Bifidobacterium and Lactobacillus positively affect AD/PD and cancer;
  • Ruminococcaceae, Prevotellaceae, and Prevotella significantly improve on AD/PD but harm cancer; and
  • Blautia has universal anticancer ability, but it may aggravate AD pathology.

1-s2.0-S0753332221011276-gr1_lrg

This may partially explain the antagonistic relationship between neurodegenerative diseases and cancer. When some individuals suffer from one disease, their intestinal flora change to obtain a stronger resistance to the other disease than healthy individuals, which is consistent with statistical data.”

https://www.sciencedirect.com/science/article/pii/S0753332221011276 “Composition of intestinal flora affects the risk relationship between Alzheimer’s disease/Parkinson’s disease and cancer”


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Offspring brain effects from maternal adversity

This 2021 rodent study investigated conception through weaning effects on offspring from stressing their mothers:

“We investigated consequences of two prenatal insults, prenatal alcohol exposure (PAE) and food-related stress, on DNA methylation profiles of the rat brain during early development. We analyzed patterns in prefrontal cortex, a key brain region involved in cognition, executive function, and behavior, of both males and females, and found sex-dependent and sex-concordant influences of these insults.

The pair-fed (PF) group in the PAE model is a standard control for effects of alcohol in reducing food intake. However, compared to the PAE group that, albeit eating less, eats ad libitum, pair-feeding is a treatment in itself, with PF dams receiving a restricted ration, which results in both hunger and a disrupted feeding schedule. These stress-related effects could potentially parallel or model food scarcity or food insecurity in human populations.

We observed more DMRs (Differentially Methylated Regions) that showed decreased DNAm rather than increased DNAm in PF animals, suggesting that food-related stress may interfere with one-carbon metabolism and the pathways that deposit methylation on DNA. We also identified a sex-concordant DMR that showed decreased DNAm in PF animals in the glucocorticoid receptor Nr3c1, which plays a key role in stress responsivity and may reflect a reprogramming of the stress response.

This result is in line with previous studies that have shown that pair-feeding is a considerable stressor on dams, with lasting consequences on development, behavior, and physiology of their offspring. Altered DNAm of this key HPA axis gene may reflect broader alterations to stress response systems, which may in turn, influence programming of numerous physiological systems linked to the stress response, including immune function, metabolic processes, and circadian rhythms.

In PAE and PF animals compared to controls, we identified 26 biological pathways that were enriched in females, including those involved in cellular stress and metabolism, and 10 biological pathways enriched in males, which were mainly involved in metabolic processes. These findings suggest that PAE and restricted feeding, both of which act in many respects as prenatal stressors, may influence some common biological pathways, which may explain some of the occasional overlap between their resulting phenotypes.

genes-12-01773-g005

This study highlights the complex network of neurobiological pathways that respond to prenatal adversity/stressors and that modulate differential effects of early life insults on functional and health outcomes. Study of these exposures provides a unique opportunity to investigate sex-specific effects of prenatal adversity on epigenetic patterns, as possible biological mechanisms underlying sex-specific responses to prenatal insults are understudied and remain largely unknown.”

https://www.mdpi.com/2073-4425/12/11/1773/htm “Prenatal Adversity Alters the Epigenetic Profile of the Prefrontal Cortex: Sexually Dimorphic Effects of Prenatal Alcohol Exposure and Food-Related Stress”


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Week 87 of Changing to a youthful phenotype with sprouts

This week I dialed back eating microwaved 3-day-old broccoli / red cabbage / mustard sprouts from twice a day to once a day. For my reasoning, here are two papers on broccoli sprouts and thyroid function, with the first a 2018 human study:

“We analyzed biochemical measures of thyroid function and thyroid autoimmunity in a subset of participants in a broccoli sprout clinical trial. The present work is a retrospective analysis of a subset of serum samples collected during a clinical trial conducted from mid-October 2011 to early January 2012.

130 individuals received placebo beverage, and 137 received broccoli sprout beverage for 84 consecutive days (12 weeks). Blood samples from day 0 and day 84 were analyzed in a subset of 45 female participants (19 placebo, 26 broccoli sprout beverage) for serum thyroid-stimulating hormone (TSH), free thyroxine (fT4), thyroglobulin (TG), anti-TG, and anti-thyroid peroxidase (anti-TPO) antibodies.

The percentage of patients with subclinical hypothyroidism (elevated TSH with normal fT4) was not significantly different between the two groups either before or after treatment.

subclinical hypothyroidism

Daily ingestion of a broccoli sprout extract beverage over 84 days had no deleterious effect on thyroid function tests or measures of thyroid autoimmunity. It may be prudent to evaluate thyroidal safety of plant-based food supplements on a case-by-case basis.”

https://www.sciencedirect.com/science/article/abs/pii/S0278691519300547 “Broccoli sprout beverage is safe for thyroid hormonal and autoimmune status: Results of a 12-week randomized trial” (not freely available)


A 2020 review by three of these coauthors summarized further details:

“One difference between the thyroid and other tissues is that ROS are not primarily a byproduct of its physiology, but an indispensable part of it. Thyroid follicular cells actively produce H2O2 to facilitate a cascade of redox reactions that sequentially oxidize iodide, iodinate tyrosine residues within Tg, and couple iodinated tyrosine residues of Tg to each other to form T4 and T3 (triiodothyronine).

There exists a fail-safe mechanism in which specific combinations of four Keap1 cysteines can form a disulfide bond to sense H2O2. This sensing mechanism appears to be distinct from that triggered by other Nrf2 inducers, such as electrophiles.

Findings from Keap1KD mice suggest that chronic genetic activation of Nrf2 signaling may have negative consequences for the thyroid gland. However, analysis of data from a clinical trial has shown that consumption of a broccoli sprout beverage (yielding pharmacologically active amounts of the Nrf2-activating compound sulforaphane) is safe for thyroid hormonal and autoimmune status during a 12-week administration period.

Nevertheless, it appears prudent to monitor thyroid function and thyroid volume (at least by palpation) in patients treated with Nrf2-modulating compounds in clinical trials or clinical practice.”

https://www.mdpi.com/2076-3921/9/11/1082/htm “The Keap1/Nrf2 Signaling Pathway in the Thyroid—2020 Update”


My Day 70 lab results for inflammation markers were great:

IL-6 2020

A year later, IL-6 was below the test’s detection limit, and high-sensitivity C-reactive protein could hardly have been better at 0.24 mg/L.

But TSH (reference interval 0.45 – 4.50 μIU/mL) increased from 3.01 to 7.50. Here’s what Labcorp Technical Review L8186 said:

“The panel concluded that despite the fact that serum TSH concentrations higher than 2.5 μIU/mL but less than 4.5 μIU/mL may identify some individuals with the earliest stage of hypothyroidism, there is no evidence for associated adverse consequences. Additionally, consequences of subclinical hypothyroidism with serum TSH levels between 4.5 μIU/mL and 10 μIU/mL are minimal, and the panel recommends against routine treatment of patients with TSH levels in these ranges.”

I went in last weekend to retest. Although the provider verbally agreed to test TSH, free T3, and free T4, a different test was ordered.

TSH was still high at 5.85 μIU/mL. Other measurements (Total T4, T3 Uptake, and Free Thyroxine Index) aren’t suitable substitutes for free T3 and free T4. I’ll specify Labcorp test numbers next time.


My hypothesis is that preconditioning my endogenous ARE system twice daily worked alright elsewhere, but not for my thyroid. We’ll find out in 2022 whether halving the electrophilic activations of my Nrf2 signaling pathway has any effect on thyroid measurements.

I don’t take anything with, or an hour before or after these very reactive isothiocyanates. I continue to eat 3-day-old oat sprouts twice a day with other foods.

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Eat oats and inulin to reverse effects of circadian disruption

This 2021 rodent study induced metabolic syndrome with a high-fat diet and switching light-dark cycles every week for 14 weeks. While continuing to disrupt circadian rhythms for ten more weeks, most metabolic effects were reversed by adding either 5% β-glucan, 5% inulin, or .05% melatonin to subjects’ high-fat diet:

“Both prebiotics (oat β-glucan and chicory inulin) and melatonin significantly reversed circadian disruption-induced metabolic syndrome (CDIMS) and alteration of gut microbiota composition. Both prebiotics also reversed increase in body weight and liver weight-to-body weight ratio, and decrease in fasting plasma insulin. Only oat β-glucan reduced plasma leptin and alleviated glucose intolerance.

body weight

All dietary interventions enhanced species richness. In altering gut microbiota, oat β-glucan reversed populations of 7 bacterial genera and increased butyrate producers including Ruminococcaceae and Lachnospiraceae which enhance gut barrier protection and regulate glucose homeostasis.

Though melatonin cannot be fermented in the gut as prebiotics, oral administration of exogenous melatonin absorbed via melatonin receptors concentrated in the intestine has been demonstrated for its effects on shaping gut microbiota. There is currently no concrete mechanism explaining how melatonin affects gut microbial ecology. We postulate that the ability of melatonin to alleviate CDIMS is not governed by changes of SCFAs, but possibly a direct host effect which subsequently affects other metabolites such as bile acids.

In contrast with melatonin, oligomeric chicory inulin as a fermentable fiber mainly affects gut microbiota which affects the host indirectly. For polymeric oat β-glucan, our results suggested that it is probably a combination of both direct and indirect effects to the host, and this is a special property not yet evidenced in other polysaccharides.

Approximately 35% of human gut microbiota undergo temporal rhythmicity. We speculate that prebiotics may affect diurnal oscillations of gut microbiota, its capacity for energy harvest and production of metabolites, which subsequently affect host central circadian clocks through gut-microbiome-brain axis, in which gut microbes interact with central nervous system via nervous, endocrine, and immune signaling pathways.”

https://www.sciencedirect.com/science/article/abs/pii/S0144861721006032 “Circadian disruption-induced metabolic syndrome in mice is ameliorated by oat β-glucan mediated by gut microbiota” (not freely available)


Humans could avoid a high-fat diet, of course. My main experiences with circadian disruptions were 18-hour days of submarine life. That didn’t cause metabolic syndrome, just disorientation to the real world after surfacing.

The end of fig season

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Epigenetic clocks so far in 2021

2021’s busiest researcher took time out this month to update progress on epigenetic clocks:

Hallmarks of aging aren’t all associated with epigenetic aging.

epigenetic aging vs. hallmarks of aging

Interventions that increase cellular lifespan aren’t all associated with epigenetic aging.

epigenetic aging vs. cellular lifespan

Many of his authored or coauthored 2021 papers developed human / mammalian species relative-age epigenetic clocks.

epigenetic clock mammalian maximum lifespan

Relative-age epigenetic clocks better predict human results from animal testing.

pan-mammalian epigenetic clock


Previously curated papers that were mentioned or relevant included:

All about vasopressin

This 2021 review subject was vasopressin:

“Vasopressin is a ubiquitous molecule playing an important role in a wide range of physiological processes, thereby implicated in pathomechanisms of many disorders. The most striking is its central effect in stress-axis regulation, as well as regulating many aspects of our behavior.

Arginine-vasopressin (AVP) is a nonapeptide that is synthesized mainly in the supraoptic, paraventricular (PVN), and suprachiasmatic nucleus of the hypothalamus. AVP cell groups of hypothalamus and midbrain were found to be glutamatergic, whereas those in regions derived from cerebral nuclei were mainly GABAergic.

In the PVN, AVP can be found together with corticotropin-releasing hormone (CRH), the main hypothalamic regulator of the HPA axis. The AVPergic system participates in regulation of several physiological processes, from stress hormone release through memory formation, thermo- and pain regulation, to social behavior.

vasopressin stress axis

AVP determines behavioral responses to environmental stimuli, and participates in development of social interactions, aggression, reproduction, parental behavior, and belonging. Alterations in AVPergic tone may be implicated in pathology of stress-related disorders (anxiety and depression), Alzheimer’s, posttraumatic stress disorder, as well as schizophrenia.

An increasing body of evidence confirms epigenetic contribution to changes in AVP or AVP receptor mRNA level, not only during the early perinatal period, but also in adulthood:

  • DNA methylation is more targeted on a single gene; and it is better characterized in relation to AVP;
  • Some hint for bidirectional interaction with histone acetylation was also described; and
  • miRNAs are implicated in the hormonal, peripheral role of AVP, and less is known about their interaction regarding behavioral alteration.”

https://www.mdpi.com/1422-0067/22/17/9415/htm “Epigenetic Modulation of Vasopressin Expression in Health and Disease”


Find your way, regardless of what the herd does.

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Preventing human infections with dietary fibers

This 2020 review covered interactions of gut microbiota, intestinal mucus, and dietary fibers. I’ve outlined its headings and subheadings, and ended with its overview:

“I. Dietary fibers and human mucus-associated polysaccharides: can we make an analogy?

I.1 Brief overview of dietary fibers and mucus polysaccharides structures and properties

I.I.1 Dietary fibers

  • Dietary fiber intake and health effects

I.I.2 Intestinal mucus polysaccharides

  • Structure
  • Main functions

I.2 Similarities and differences between dietary fibers and mucus carbohydrates

  • Origin and metabolism
  • Structure

II. Interactions of dietary fibers and mucus-associated polysaccharides with human gut microbiota

II-1 Substrate accessibility and microbial niches

  • Dietary fibers
  • Mucus polysaccharides

II-2 Recognition and binding strategies

  • Dietary fibers
  • Mucus polysaccharides

II-3 Carbohydrate metabolism by human gut microbiota

II-3.1 Specialized carbohydrate-active enzymes

II-3.2 Vertical ecological relationships in carbohydrate degradation

  • Dietary fibers
  • Mucus polysaccharides

II-3.3 Horizontal ecological relationships in carbohydrate degradation

II.4 Effect of carbohydrates on gut microbiota composition and sources of variability

II.4.1 Well-known effect of dietary fibers on the gut microbiota

II.4.2 First evidences of a link between mucus polysaccharides and gut microbiota composition

III. Gut microbiota, dietary fibers and intestinal mucus: from health to diseases?

[no III.1]

III.2 Current evidences for the relationship between dietary fibers, mucus and intestinal-inflammatory related disorder

III.2.1 Obesity and metabolic-related disorders

  • Dietary fibers
  • Mucus polysaccharides

III.2.2 Inflammatory bowel diseases

  • Dietary fibers
  • Mucus polysaccharides

III.2.3 Colorectal cancer

  • Dietary fibers
  • Mucus polysaccharides

IV. How enteric pathogens can interact with mucus and dietary fibers in a complex microbial background?

IV.1 Mucus-associated polysaccharides: from interactions with enteric pathogens to a cue for their virulence?

IV.1.1 Pathogens binding to mucus

  • Binding structures
  • Sources of variations

IV.1.2 Mucus degradation by pathogens

  • Bacterial mucinases
  • Glycosyl hydrolases

IV.1.3 Mucus-based feeding of pathogens

  • Primary degraders or cross-feeding strategies
  • Importance of microbial background

IV.1.4 Pathogens and inflammation in a mucus-altered context

IV.1.5 Modulation of virulence genes by mucus degradation products

IV.2 How can dietary fiber modulate enteric pathogen virulence?

IV.2.1 Direct antagonistic effect of dietary fibers on pathogens

  • Bacteriostatic effect
  • Inhibition of cell adhesion
  • Inhibition of toxin binding and activity

IV.2.2 Indirect effect of dietary fibers through gut microbiota modulation

  • Modulation of microbiota composition
  • Modulation of gut microbiota activity

IV.2.3 Inhibition of pathogen interactions with mucus: a new mode of dietary fibers action?

  • Binding to mucus: dietary fibers acting as a decoy
  • Inhibition of mucus degradation by dietary fibers

V. Human in vitro gut models to decipher the role of dietary fibers and mucus in enteric infections: interest and limitations?

V.1 Main scientific challenges to be addressed

V.2 In vitro human gut models as a relevant alternative to in vivo studies

V.3 In vitro gut models to decipher key roles of digestive secretions, mucus and gut microbiota

V.4 Toward an integration of host responses

V.5 From health to disease conditions

dietary fibers prevent infections

Overview of the potential role of dietary fibers in preventing enteric infections. Reliable and converging data from scientific literature are represented with numbers in circles, while data more hypothetical needing further investigations are represented with numbers in squares.

  1. Some dietary fibers exhibit direct bacteriostatic effects against pathogens.
  2. Dietary fiber degradation leads to short-chain fatty acids (SCFAs) production that can modulate pathogens’ virulence.
  3. By presenting structure similarities with receptors, some dietary fibers can prevent pathogen adhesin binding to their receptors.
  4. By the same competition mechanism, dietary fibers can also prevent toxins binding to their receptors.
  5. Dietary fibers are able to promote gut microbiota diversity.
  6. Dietary fibers may promote growth of specific strains with probiotic properties and therefore exhibit anti-infectious properties.
  7. Suitable dietary fiber intake prevents microbiota’s switch to mucus consumption, limiting subsequent commensal microbiota encroachment and associated intestinal inflammation.
  8. Dietary fibers may prevent pathogen cross-feeding on mucus by limiting mucus degradation and/or by preserving diversity of competing bacterial species.
  9. By preventing mucus over-degradation by switcher microbes, dietary fibers can hamper pathogen progression close to the epithelial brush border, and further restrict subsequent inflammation.”

https://doi.org/10.1093/femsre/fuaa052 “Tripartite relationship between gut microbiota, intestinal mucus and dietary fibers: towards preventive strategies against enteric infections” (not freely available)


There were many links among gut microbiota studies previously curated. For example, Go with the Alzheimer’s Disease evidence found:

“Akkermansia cannot always be considered a potentially beneficial bacterium. It might be harmful for the gut–brain axis in the context of AD development in the elderly.”

The current review provided possible explanations:

“Akkermansia muciniphila could be considered as a species that fulfills a keystone function in mucin degradation. It is a good example of a mucus specialist.”

Points #7-9 of the above overview inferred that insufficient dietary fiber may disproportionately increase abundance of this species. But Gut microbiota strains also found that effects may be found only below species at species’ strain levels.

These reviewers provided copies in places other than what’s linked above. Feel free to contact them for a copy.


Moon bandit

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No magic bullet, only magical thinking

Consider this a repost of Dr. Paul Clayton’s blog post The Drugs Don’t Work:

“The drug industry has enough funds to:

  • Rent politicians;
  • Subvert regulatory agencies;
  • Publish fake data in the most august peer-reviewed literature; and
  • Warp the output of medical schools everywhere.

Their products are a common cause of death. Every year, America’s aggressively modern approach to disease kills over 100,000 in-hospital patients, and twice that number of out-patients.

In 1900, a third of all deaths occurred in children under the age of 5. By 2000 this had fallen to 1.4%. The resulting 30-year increase in average life expectancy fed into the seductive and prevailing myth that we are all living longer; which is manifestly untrue. Improvements in sanitation were far more significant in pushing infections back than any medical developments.

There is currently no pharmaceutical cure for Alzheimer’s or Parkinsonism, nor can there be when these syndromes are in most cases driven by multiple metabolic distortions caused by today’s diet. The brain is so very complex, and it can go wrong in so many ways. The idea that we can find a magic bullet for either of these syndromes is ill-informed and philosophically mired in the past.

It is also dangerous. There is a significant sub-group of dementia sufferers whose conditions are driven and exacerbated by pharmaceuticals. Chronic use of a number of commonly prescribed drugs – and ironically, anti-Parkinson drugs – increases the risk of dementia by roughly 50%.

Big Pharma’s ability to subvert regulatory authorities is even more dangerous. The recent FDA approval of Biogen’s drug aducanumab is a scandal; not one member of the FDA Advisory Committee voted to approve this ineffective product, and three of them resigned in the aftermath of the FDA’s edict. This ‘anti-Alzheimer’s’ drug, which will earn Biogen $56,000 / patient / year, was licensed for financial reasons; it reduced amyloid plaque but was clinically ineffective.

So did the eagerly awaited gantenerumab and solanezumab. But they, too, failed to produce any significant clinical benefit.”


A knee-replacement patient enduring her daily workout

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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”


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Gut and brain health

This 2021 human review subject was interactions of gut health and disease with brain health and disease:

“Actions of microbial metabolites are key for appropriate gut-brain communication in humans. Among these metabolites, short-chain fatty acids (SCFAs), tryptophan, and bile acid metabolites / pathways show strong preclinical evidence for involvement in various aspects of brain function and behaviour.

Dietary fibres, proteins, and fats ingested by the host contain components which are metabolized by microbiota. SCFAs are produced from fermentation of fibres, and tryptophan-kynurenine (TRP-KYN) metabolites from dietary proteins. Primary bile acids derived from liver metabolism aid in lipid digestion, but can be deconjugated and bio-transformed into secondary bile acids.

1-s2.0-S0149763421001032-gr1

One of the greatest challenges with human microbiota studies is making inferences about composition of colonic microbiota from faeces. There are known differences between faecal and caecal microbiota composition in humans along with spatial variation across the gastrointestinal tract.

It is difficult to interpret microbiome-host associations without identifying the driving influence in such an interaction. Large cohort studies may require thousands of participants on order to reach 20 % explanatory power for a certain host-trait with specific microbiota-associated metrics (Shannon diversity, relative microbial abundance). Collection of metadata is important to allow for a better comparison between studies, and to identify differentially abundant microbes arising from confounding variables.”

https://www.sciencedirect.com/science/article/pii/S0149763421001032 “Mining Microbes for Mental Health: Determining the Role of Microbial Metabolic Pathways in Human Brain Health and Disease”


Don’t understand why these researchers handcuffed themselves by only using PubMed searches. For example, two papers were cited for:

“Conjugated and unconjugated bile acids, as well as taurine or glycine alone, are potential neuroactive ligands in humans.”

Compare scientific coverage of PubMed with Scopus:

  • 2017 paper: PubMed citations 39; Scopus citations 69.
  • 2019 paper: PubMed citations 69; Scopus citations 102.

Large numbers of papers intentionally missing from PubMed probably influenced this review’s findings, such as:

  1. “There are too few fibromyalgia and migraine microbiome-related studies to make definitive conclusions. However, one fibromyalgia study found altered microbial species associated with SCFA and tryptophan metabolism, as well as changes in serum levels of SCFAs. Similarly, the sole migraine-microbiota study reported an increased abundance of the kynurenine synthesis GBM (gut-brain module).
  2. Due to heterogeneity of stroke and vascular disease conditions, it is difficult to make substantial comparisons between studies. There is convincing evidence for involvement of specific microbial genera / species and a neurovascular condition in humans. However, taxa were linked to LPS biosynthesis rather than SCFA production.
  3. Several studies suggest lasting microbial changes in response to prenatal or postnatal stress, though these do not provide evidence for involvement of SCFA, tryptophan, or bile-acid modifying bacteria. Similar to stress, there are very few studies assessing impact of post-traumatic stress disorder on microbiota.”

These researchers took on a difficult task. Their study design could have been better.


PXL_20210628_095746132

Wildlife

PXL_20210710_100826663

Take acetyl-L-carnitine for early-life trauma

This 2021 rodent study traumatized female mice during their last 20% of pregnancy, with effects that included:

  • Prenatally stressed pups raised by stressed mothers had normal cognitive function, but depressive-like behavior and social impairment;
  • Prenatally stressed pups raised by control mothers did not reverse behavioral deficits; and
  • Control pups raised by stressed mothers displayed prenatally stressed pups’ behavioral phenotypes.

Acetyl-L-carnitine (ALCAR) protected against and reversed depressive-like behavior induced by prenatal trauma:

alcar regime

ALCAR was supplemented in drinking water of s → S mice either from weaning to adulthood (3–8 weeks), or for one week in adulthood (7–8 weeks). ALCAR supplementation from weaning rendered s → S mice resistant to developing depressive-like behavior.

ALCAR supplementation for 1 week during adulthood rescued depressive-like behavior. One week after ALCAR cessation, however, the anti-depressant effect of ALCAR was diminished.

Intergenerational trauma induces social deficits and depressive-like behavior through divergent and convergent mechanisms of both in utero and early-life parenting environments:

  • We establish 2-HG [2-hydroxyglutaric acid, a hypoxia and mitochondrial dysfunction marker, and an epigenetic modifier] as an early predictive biomarker for trauma-induced behavioral deficits; and
  • Demonstrate that early pharmacological correction of mitochondria metabolism dysfunction by ALCAR can permanently reverse behavioral deficits.”

https://www.nature.com/articles/s42003-021-02255-2 “Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction”


Previously curated studies cited were:

This study had an effusive endorsement of acetyl-L-carnitine in its Discussion section, ending with:

“This has the potential to change lives of millions of people who suffer from major depression or have risk of developing this disabling disorder, particularly those in which depression arose from prenatal traumatic stress.”

I take a gram daily. Don’t know about prenatal trauma, but I’m certain what happened during my early childhood.

I asked both these researchers and those of Reference 70 for their estimates of a human equivalent to “0.3% ALCAR in drinking water.” Will update with their replies.


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The brainstem’s parabrachial nucleus

I often reread blog posts that you read. Yesterday, a reader clicked Treat your gut microbiota as one of your organs. On rereading, I saw that I didn’t properly reference the parabrachial nucleus as being part of the brainstem.

A “parabrachial nucleus” search led me to a discussion of two 2020 rodent studies:

“Nociceptive signals entering the brain via the spinothalamic pathway allow us to detect location and intensity of a painful sensation. But, at least as importantly, nociceptive inputs also reach other brain regions that give pain its emotional texture.

Key to that circuitry is the parabrachial nucleus (PBN), a tiny cluster of cells in the brainstem associated with homeostatic regulation of things like temperature and food intake, response to aversive stimuli, and perceptions of many kinds. Two new papers advance understanding of PBN’s role in pain:

  1. The PBN receives inhibitory inputs from GABAergic neurons in the central nucleus of the amygdala (CeA). Those inputs are diminished in chronic pain conditions, leading to PBN hyperactivity and increased pain perception. Disinhibition of the amygdalo-parabrachial pathway may be crucial to establishing chronic pain.
  2. The dorsal PBN is the first receiver of spinal nociceptive input. It transmits certain inputs to the ventral medial hypothalamus and lateral periaqueductal gray. Certain of its neurons transmit noxious inputs to the external lateral PBN, which then transmits those inputs to the CeA and bed nucleus of the stria terminalis. This is quite new, that nociceptive information the CeA receives has already been processed by the PBN. They measured many pain-related behaviors: place aversion, avoidance, and escape. That allowed them to dissect different pain-related behaviors in relation to distinct subnuclei of the PBN.

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Chronic pain is manufactured by the brain. It’s not a one-way process driven by something coming up from the periphery. The brain is actively constructing a chronic pain state in part by this recurring circuit.

A role of the PBN is to sound an alarm when an organism is in danger, but its roles go further. It is a key homeostatic center, weighing short-term versus long-term survival. If you’re warm, fed, and comfortable, organisms can address long-term directives like procreation. When you’re unsafe, though, you need to put those things off and deal with the emergency.”

https://www.painresearchforum.org/news/147704-parabrachial-nucleus-takes-pain-limelight “The Parabrachial Nucleus Takes the Pain Limelight”

https://www.jneurosci.org/content/40/17/3424 “An Amygdalo-Parabrachial Pathway Regulates Pain Perception and Chronic Pain”

https://www.sciencedirect.com/science/article/pii/S089662732030221X “Divergent Neural Pathways Emanating from the Lateral Parabrachial Nucleus Mediate Distinct Components of the Pain Response”


Two dozen papers have since cited these two studies. One that caught my eye was a 2021 rodent study:

“Migraines cause significant disability and contribute heavily to healthcare costs. Irritation of the meninges’ outermost layer (the dura mater), and trigeminal ganglion activation contribute to migraine initiation.

Dura manipulation in humans during neurosurgery is often painful, and dura irritation is considered an initiating factor in migraine. In rodents, dura irritation models migraine-like symptoms.

Maladaptive changes in central pain-processing regions are also important in maintaining pain. The parabrachial complex (PB) receives diverse sensory information, including a direct input from the trigeminal ganglion.

PB-projecting trigeminal ganglion neurons project also to the dura. These neurons represent a direct pathway between the dura, a structure implicated in migraine, and PB, a key node in chronic pain and aversion.”

https://www.sciencedirect.com/science/article/pii/S2452073X21000015 “Parabrachial complex processes dura inputs through a direct trigeminal ganglion-to-parabrachial connection”


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The amino acid ergothioneine

A trio of papers on ergothioneine starts with a 2019 human study. 3,236 people without cardiovascular disease and diabetes mellitus ages 57.4 ± 6.0 were measured for 112 metabolites, then followed-up after 20+ years:

“We identified that higher ergothioneine was an independent marker of lower risk of cardiometabolic disease and mortality, which potentially can be induced by a specific healthy dietary intake.

overall mortality and ergothioneine

Ergothioneine exists in many dietary sources and has especially high levels in mushrooms, tempeh, and garlic. Ergothioneine has previously been associated with a higher intake of vegetables, seafood and with a lower intake of solid fats and added sugar as well as associated with healthy food patterns.”

https://heart.bmj.com/content/106/9/691 “Ergothioneine is associated with reduced mortality and decreased risk of cardiovascular disease”


I came across this study by its citation in a 2021 review:

“The body has evolved to rely on highly abundant low molecular weight thiols such as glutathione to maintain redox homeostasis but also play other important roles including xenobiotic detoxification and signalling. Some of these thiols may also be derived from diet, such as the trimethyl-betaine derivative of histidine, ergothioneine (ET).

image description

ET can be found in most (if not all) tissues, with differential rates of accumulation, owing to differing expression of the transporter. High expression of the transporter, and hence high levels of ET, is observed in certain cells (e.g. blood cells, bone marrow, ocular tissues, brain) that are likely predisposed to oxidative stress, although other tissues can accumulate high levels of ET with sustained administration. This has been suggested to be an adaptive physiological response to elevate ET in the damaged tissue and thereby limit further injury.”

https://www.sciencedirect.com/science/article/pii/S2213231721000161 “Ergothioneine, recent developments”


The coauthors of this review were also coauthors of a 2018 review:

“Ergothioneine is avidly taken up from the diet by humans and other animals through a transporter, OCTN1. Ergothioneine is not rapidly metabolised, or excreted in urine, and has powerful antioxidant and cytoprotective properties.

ergothioneine in foods

Effects of dietary ET supplementation on oxidative damage in young healthy adults found a trend to a decrease in oxidative damage, as detected in plasma and urine using several established biomarkers of oxidative damage, but no major decreases. This could arguably be a useful property of ET: not interfering with important roles of ROS/RNS in healthy tissues, but coming into play when oxidative damage becomes excessive due to tissue injury, toxin exposure or disease, and ET is then accumulated.”

https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1873-3468.13123 “Ergothioneine – a diet-derived antioxidant with therapeutic potential”


I’m upping a half-pound of mushrooms every day to 3/4 lb. (340 g). Don’t think I could eat more garlic than the current six cloves.

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I came across this subject in today’s video: