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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Take taurine for your mitochondria

This 2021 review summarized taurine’s beneficial effects on mitochondrial function:

“Taurine supplementation protects against pathologies associated with mitochondrial defects, such as aging, mitochondrial diseases, metabolic syndrome, cancer, cardiovascular diseases and neurological disorders. Potential mechanisms by which taurine exerts its antioxidant activity in maintaining mitochondria health include:

  1. Conjugates with uridine on mitochondrial tRNA to form a 5-taurinomethyluridine for proper synthesis of mitochondrial proteins (mechanism 1), which regulates the stability and functionality of respiratory chain complexes;
  2. Reduces superoxide generation by enhancing the activity of intracellular antioxidants (mechanism 2);
  3. Prevents calcium overload and prevents reduction in energy production and collapse of mitochondrial membrane potential (mechanism 3);
  4. Directly scavenges HOCl to form N-chlorotaurine in inhibiting a pro-inflammatory response (mechanism 4); and
  5. Inhibits mitochondria-mediated apoptosis by preventing caspase activation or by restoring the Bax/Bcl-2 ratio and preventing Bax translocation to the mitochondria to promote apoptosis.

taurine mechanisms

An analysis on pharmacokinetics of oral supplementation (4 g) in 8 healthy adults showed a baseline taurine content in a range of 30 μmol to 60 μmol. Plasma content increased to approximately 500 μmol 1.5 h after taurine intake. Plasma content subsequently decreased to baseline level 6.5 h after intake.

We discuss antioxidant action of taurine, particularly in relation to maintenance of mitochondria function. We describe human studies on taurine supplementation in several mitochondria-associated pathologies.”

https://www.mdpi.com/1420-3049/26/16/4913/html “The Role of Taurine in Mitochondria Health: More Than Just an Antioxidant”


I take a gram of taurine at breakfast and at dinner along with other supplements and 3-day-old Avena sativa oat sprouts. Don’t think my other foods’ combined taurine contents are more than one gram, because none are found in various top ten taurine-containing food lists.

As a reminder, your mitochondria come from your mother, except in rare cases.

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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A time to speak

“To every thing there is a season, and a time to every purpose under heaven:
A time to break down, and a time to build up;
A time to mourn, and a time to dance;
A time to embrace, and a time to refrain from embracing;
A time to keep silent, and a time to speak.”


A review from 2017:

“Few, if any, other drugs can rival ivermectin for its beneficial impact on human health and welfare. Perhaps more than any other drug, ivermectin is a drug for the world’s poor. For most of this century, some 250 million people have been taking it.

The following are an indication of disease-fighting potential that has been identified for ivermectin thus far:

  • Antiviral – Ivermectin has been found to potently inhibit replication of yellow fever virus, with EC50 values in the sub-nanomolar range. It inhibits replication in several other flaviviruses, including dengue, Japanese encephalitis, and tick-borne encephalitis. Ivermectin interrupts virus replication. It demonstrates antiviral activity against several RNA viruses by blocking nuclear trafficking of viral proteins. It has been shown to have potent antiviral action against HIV-1.
  • Asthma – Ivermectin suppressed mucus hypersecretion by goblet cells, establishing that ivermectin can effectively curb inflammation, such that it may be useful in treating allergic asthma and other inflammatory airway diseases.
  • Bedbugs – Ivermectin is highly effective against bedbugs, capable of eradicating or preventing bedbug infestations.
  • Disease vector control – Ivermectin is highly effective in killing a broad range of insects. Comprehensive testing against 84 species of insects showed that avermectins were toxic to almost all insects tested. At sub-lethal doses, ivermectin inhibits feeding and disrupts mating behavior, oviposition, egg hatching, and development.
  • Malaria – Mosquitoes that transmit Plasmodium falciparum, the most dangerous malaria-causing parasite, can be killed by ivermectin present in the human bloodstream after a standard oral dose.
  • Myiasis – Myiasis is an infestation of fly larvae that grow inside the host. Oral myiasis has been successfully treated with ivermectin, which has also been effective as a non-invasive treatment for orbital myiasis, a rare and preventable ocular morbidity.
  • Schistosomiasis – Schistosoma species are the causative agent of schistosomiasis, a disease afflicting more than 200 million people worldwide. Ivermectin helps control one of the world’s major neglected tropical diseases.
  • Trichinosis – Globally, approximately 11 million individuals are infected with Trichinella roundworms. Ivermectin kills Trichinella spiralis, the species responsible for most of these infections.”

https://www.nature.com/articles/ja201711 “Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations”


59 citations in CrossRef. Didn’t see citing 2020-2021 papers that noted any safety concerns when administered at proper doses.

Train your immune system every day, because:

“Rapid clearance following ivermectin dosing, results not from direct impact of the drug, but via suppression of a parasite’s ability to evade the host’s natural immune defense mechanisms.”

It’s safe, and it’s effective. Ivermectin’s main difficulty is that its patent expired in 1997.

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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.


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Wildlife

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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.

1Inline2

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.

PXL_20210606_095517049

I came across this subject in today’s video:

Does sulforaphane treat autism?

A 2021 human study investigated sulforaphane treatments of autistic 3-to-12-year-olds:

“Sulforaphane (SF) led to non-statistically significant changes in the total and all subscale scores of the primary outcome measure. Several effects of SF on biomarkers correlated to clinical improvements. SF was very well tolerated and safe and effective based on our secondary clinical measures.

13229_2021_447_Fig1

Clinical response to SF was associated with changes in mitochondrial function, and large intrasubject variability in this study was linked to underlying biological responses. The increase in ATP [adenosine triphosphate]-Linked Respiration associated with improvement in ABC [Aberrant Behavior Checklist] scores suggests that those individuals who showed improvements in behavior also had improved mitochondrial capacity to produce ATP.

Individuals who showed an improvement in ABC scores also showed a decrease in Proton Leak Respiration, suggesting that their mitochondria were better able to regulate oxidative stress. It is also possible that the increase in ATP production was related to improvement in the ability of mitochondria to handle oxidative stress.

SF had significant positive effects on oxidative stress, cytoprotective markers and cytokines, as well as mitochondrial function. These were promising findings that require further investigation of both clinical effects and mechanisms of action of SF.”

https://molecularautism.biomedcentral.com/articles/10.1186/s13229-021-00447-5 “Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder”


Differences between this clinical trial and its pilot study curated in Autism biomarkers and sulforaphane included:

“HO-1 [heme oxygenase 1] functions to couple activation of mitochondrial biogenesis to anti-inflammatory cytokine expression. It was initially increased in the pilot study, then paradoxically decreased in the main study, on continued treatment for longer periods with SF.

Increased HO-1 is consistent with decreases in proinflammatory cytokines we observed initially in IL-6, IL-1β and TNF-α. Decreased levels of cytokines continued after HO-1 returned to baseline with longer duration of treatment and suggest a decreased inflammatory state.

These cytokines are usually elevated in children with ASD, but were decreased on treatment with SF: IL-6 and TNF-α at 15 (but not 30) weeks.”

This study made a good effort with autistic children. Its insignificant effects of sulforaphane treatments pointed toward an understanding that human experiences when we are fetuses can override many subsequent events, treatments, and life experiences.

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.

One aspect of research on short-chain fatty acids

To further understand An overlooked gut microbiota product, a 2018 rodent study found:

“Microbial metabolites short-chain fatty acids (SCFAs) have been implicated in gastrointestinal functional, neuroimmune regulation, and host metabolism, but their role in stress-induced behavioural and physiological alterations is poorly understood

SCFAs are primarily derived from fermentation of dietary fibres, and play a pivotal role in host gut, metabolic and immune function. All these factors have previously been demonstrated to be adversely affected by stress.

Administration of SCFAs to mice undergoing psychosocial stress alleviated enduring alterations in anhedonia and heightened stress-responsiveness, as well as stress-induced increases in intestinal permeability.

experimental design

SCFA treatment alleviated psychosocial stress-induced alterations in reward-seeking behaviour, and increased responsiveness to an acute stressor and in vivo intestinal permeability. In addition, SCFAs exhibited behavioural test-specific antidepressant and anxiolytic effects, which were not present when mice had also undergone psychosocial stress.”

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP276431 “Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain–gut axis alterations”


One way researchers advance science is to relate aspects of their findings to previous studies. That approach works, but may miss items that weren’t covered in previous research.

This study fed specific quantities of three SCFAs – acetate, butyrate, and propionate – apparently due to previous research findings. If other SCFAs produced by gut microbiota were ignored – like crotonate (aka unsaturated butyrate) – how would that approach advance science?

I found this study from its citation in Harnessing endogenous defenses with broccoli sprouts.

Several diseases, one treatment?

This 2021 review summarized three dietary supplements’ effects on psychiatric symptoms:

“Upregulation of Nrf2 has been suggested as a common therapeutic target for major neuropsychiatric disorders. In this paper, evidence is presented showing how NAC [N-acetyl-cysteine], coenzyme Q10 (CoQ), and melatonin can ameliorate many important effects of oxidative stress by upregulating Nrf2.

Given its key role in governing cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder, and schizophrenia. These are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide, and peroxynitrite.

CoQ:

  • Acts as a superoxide scavenger in neuroglial mitochondria;
  • Instigates mitohormesis;
  • Ameliorates lipid peroxidation in the inner mitochondrial membrane;
  • Activates uncoupling proteins;
  • Promotes mitochondrial biogenesis; and
  • Has positive effects on the plasma membrane redox system.

Melatonin:

  • Scavenges mitochondrial free radicals;
  • Inhibits mitochondrial nitric oxidesynthase;
  • Restores mitochondrial calcium homeostasis;
  • Deacetylates and activates mitochondrial SIRT3;
  • Ameliorates increased permeability of the blood-brain barrier and intestine; and
  • Counters neuroinflammation and glutamate excitotoxicity.”

https://www.researchgate.net/publication/348309816_Increasing_Nrf2_Activity_as_a_Treatment_Approach_in_Neuropsychiatry “Increasing Nrf2 Activity as a Treatment Approach in Neuropsychiatry” (registration required)


These reviewers explored three selected supplements, citing 380 references. They overlooked something, though. There was only one mention of sulforaphane in their paper, yet four references’ titles included sulforaphane?

I take two of the three exogenous supplements discussed. The one I stopped taking over a year ago – NAC – was thoroughly discussed, but not in contexts directly related to the Nrf2 transcription factor. Why?

Switch on your Nrf2 signaling pathway pointed out:

“We use NAC in the lab all the time because it stops an Nrf2 activation. So that weak pro-oxidant signal that activates Nrf2, you switch it off by giving a dose of NAC. It’s a potent antioxidant in that right, but it’s blocking signalling. And that’s what I don’t like about its broad use.”

The current review noted that Nrf2 is activated by oxidative stress. NAC is a precursor to glutathione – our main endogenous antioxidant – and neither one activates Nrf2 pathways.

What does? Sulforaphane.

PXL_20210412_104353167

Our first 1000 days

This 2021 review subject was a measurable aspect of our early lives:

“The first 1000 days from conception are a sensitive period for human development programming. During this period, environmental exposures may result in long-lasting epigenetic imprints that contribute to future developmental trajectories.

The present review reports on effects of adverse and protective environmental conditions occurring on glucocorticoid receptor gene (NR3C1) regulation in humans. Thirty-four studies were included.

The hypothalamic-pituitary-adrenal (HPA) axis is key in regulating mobilization of energy. It is involved in stress reactivity and regulation, and it supports development of behavioral, cognitive, and socio-emotional domains.

The NR3C1 gene encodes for specific glucocorticoid receptors (GRs) in the mammalian brain, and it is epigenetically regulated by environmental exposures.

When mixed stressful conditions were not differentiated for their effects on NR3C1 methylation, no significant results were obtained, which speaks in favor of specificity of epigenetic vestiges of different adverse conditions. Specific maternal behaviors and caregiving actions – such as breastfeeding, sensitive and contingent interactive behavior, and gentle touch – consistently correlated with decreased NR3C1 methylation.

If the neuroendocrine system of a developing fetus and infant is particularly sensitive to environmental stimulations, this model may provide the epigenetic basis to inform promotion of family-centered prevention, treatment, and supportive interventions for at-risk conditions. A more ambiguous picture emerged for later effects of NR3C1 methylation on developmental outcomes during infancy and childhood, suggesting that future research should favor epigenome-wide approaches to long-term epigenetic programming in humans.”

https://www.sciencedirect.com/science/article/abs/pii/S0149763421001081 “Glucocorticoid receptor gene (NR3C1) methylation during the first thousand days: Environmental exposures and developmental outcomes” (not freely available). Thanks to Dr. Livio Provenci for providing a copy.


I respectfully disagree with recommendations for an EWAS approach during infancy and childhood. What happened to each of us wasn’t necessarily applicable to a group. Group statistics may make interesting research topics, but they won’t change anything for each individual.

Regarding treatment, our individual experiences and needs during our first 1000 days should be repeatedly sensed and felt in order to be therapeutic. Those memories are embedded in our needs because cognitive aspects of our brains weren’t developed then.

To become curative, we first sense and feel early needs and experiences. Later, we understand their contributions and continuations in our emotions, behavior, and thinking.

And then we can start to change who we were made into.

Rhythmicity

This 2021 review subject was circadian signaling in the digestive system:

“The circadian system controls diurnal rhythms in gastrointestinal digestion, absorption, motility, hormones, barrier function, and gut microbiota. The master clock, located in the suprachiasmatic nucleus (SCN) region of the hypothalamus, is synchronized or entrained by the light–dark cycle and, in turn, synchronizes clocks present in peripheral tissues and organs.

Rhythmic clock gene expression can be observed in almost every cell outside the SCN. These rhythms persist in culture, indicating that these cells also contain an endogenous circadian clock system.

Processes in the gastrointestinal tract and its accessory digestive organs display 24-hour rhythmicity:

Clock disruption has been associated with disturbances in gut motility. In an 8-day randomized crossover study, in which 14 healthy young adults were subjected to simulated day-shift or night-shift sleeping schedules, circadian misalignment increased postprandial hunger hormone ghrelin levels by 10.4%.

Leptin, a satiety hormone produced by white adipose tissue, peaks at night in human plasma. A volunteer ate and slept at all phases of the circadian cycle by scheduling seven recurring 28-hour ‘days’ in dim light and eating four isocaloric meals every ‘day’. Plasma leptin levels followed the forced 28-hour behavioural cycle, while their endogenous 24-hour rhythm was lost. However, since meal timing can entrain the circadian system, this forced desynchrony study could not exclude a potential role of the circadian system.

Another constant routine protocol study with 20 healthy participants showed that rhythms in plasma lipids differed substantially between individuals, suggesting the existence of different circadian metabolic phenotypes.

Composition, function, and absolute abundance of gut microbiota oscillate diurnally. For example, microbial pathways involved in cell growth, DNA repair and energy metabolism peaked during the dark phase, while detoxification, environmental sensing and motility peaked during the day.

It is unclear how phase information is communicated to gut microbiota. However, human commensal bacterium Enterobacter aerogenes showed an endogenous, temperature-compensated 24-hour pattern of swarming and motility in response to melatonin, suggesting that the host circadian system might regulate microbiota by entraining bacterial clocks.

With increasing popularity of time-restricted eating as a dietary intervention, which entrains peripheral clocks of the gastrointestinal tract, studies investigating circadian clocks in the human digestive system are highly needed. Additionally, further research is needed to comprehend shifts in temporal relationships between different gut hormones during chronodisruption.”

https://www.nature.com/articles/s41575-020-00401-5 “Circadian clocks in the digestive system” (not freely available). Thanks to Dr. Inge Depoortere for providing a copy.


This review included many more human examples. I mainly quoted gut interactions.

A long time ago I was successively stationed on four submarines. An 18-hour schedule while underwater for weeks and months wiped out my circadian rhythms.

The U.S. Navy got around to studying 18-hour schedule effects this century. In 2014, submarine Commanding Officers were reportedly authorized to switch their crews to a 24-hour schedule.

Surface! Surface! Surface!