Tag: epigenetics

Posted on

Sorry for the disruption in site service (my fault); Cancer, POTS, Epigenetics & the One-Carbon Methylation Cycles.

I missed an email. Problem now fixed.

I have been very busy with the pomegranate paper, and sadly, or not surprising, it was not accepted for further review – non-standard, which is true. It was too long and I learned more while researching for it and needed to rewrite the main article. A book or website with guided pages and some screening questions to help guide people to material that may be helpful is my plan.

My goal is to make a more concise site with a dropdown menu of some sort to help guide people to the info that they want or need – and some screening question sections to help pinpoint which information may be needed. I have started a very preliminary workflowy.com (https://workflowy.com/s/hyperinflammation-pr/NA9NrJpva8lyi1nH) but got hung up on how to add images. It says just “drag and drop” and I have no idea why that doesn’t seem to work. Is that an Apple thing? ** I figured out how to drag and drop an image but then I couldn’t move it to any other sections. WorkFlowy may not be for me.

I have been posting on SubStack and need to post here more. I have posted a few new things to peace-is-happy.org, but an older post was most read in November so that may have been Oct or even longer ago. The images in this post are some of my travel pics. Peace is mental and physical. (peace-is-happy.org) It is not a long post but has some good starting points. Build mindfulness, peaceful brain pathways and try to forget stressful worry pathways by not thinking about them. One anxiety tip I like – make a Worry Jar and write down your worry, stick it in the jar, schedule 15 minutes to go through your Worry Jar once a week. Saves mental strain to not have an overload on your mind. Writing lists or goals can help put them someplace else where you know you can find it again, and have a little more peace of mind.

“Great design should be ‘intuitive.’ Translation: feel natural.”
— Tom Peters

Nature repeats chemical structures and pathways across the chain of life. The essential omega 3 fatty acid DHA is ancient, unchanged from simple life forms to complex.

This post is the first of a series, in which I will share my Genes Table.

It has the solution for the health problems that gene alleles may cause – plant polyphenols. Polyphenols may be able to correct the up or down regulation in important pathways that the dysfunctional allele caused by affecting microRNA.

  1. “microRNA are the real regulators of gene transcription”. – Substack.
  2. “microRNA, elevated homocysteine and is there a role for excess Retinoic Acid?” (substack.com) *The hyperhomocysteinemia/homocystinuria section of my Genes Table.
  3. “Pollutants in Human Plasma Found via Double-Filtration Plasmapheresis Plasma Exchange”, James Lyons-Weiler. (substack.com) *This is a cross post. Heavy metal toxins and thread like objects and aluminum-silicon combinations were found in a filtration of plasma procedure. This is related to pomegranate because the peel is effective at clumping nanoparticles into larger clumps that are big enough for white blood cells to sense as something needing to be removed.
  4. “POTS – Postural Orthostatic Tachycardia Syndrome, can be epigenetic & therefore may be reversible”. (substack.com) *The Dystonia section of my Genes Table.

Before moving on to more sections, or exploring other conditions and yet more links…

This one is excellent and has a video abstract/overview: (Hayden, Tyagi, 2022) Hayden, M.R., Tyagi, S.C., (2022). Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer’s Disease and Long COVID. Medicina. 58(1):16. https://doi.org/10.3390/medicina58010016 Available at https://www.mdpi.com/1648-9144/58/1/16 (Accessed: 4 Dec 2022) Figure 1: Folate-Mediated One-Carbon Metabolism (FOCM).

In it we learn that the one-carbon methylation cycles are used within cell’s cytoplasm, within the mitochondria, and within the cell’s nucleus – and if the nucleus version is impaired, then … methylation of DNA will be impaired – it will not occur. Epigenetic changes will be very likely if there is dysfunction in the one-carbon methylation cycle within the nucleus.

Nature loves a good design and will repeat it.

“Figure 2. Compartmentalization of FOCM. Note the presence of the folate-methionine one carbon cycle metabolism in the cytoplasm (cytosol), mitochondria and nucleus. Additionally, note the importance of formate being transferred from the mitochondria to the nucleus, as well as S-adenosylmethionine (SAM) via nuclear pores. Importantly, deoxythymidine monophosphate (dTMP) synthesis occurs in the cytosol, nucleus and mitochondria, whereas purine synthesis and methionine synthesis take place within the cytosol. Mitochondrial FOCM generates formate for cytosolic and nuclear FOCM and biosynthetic precursors for mtDNA synthesis and mitochondrial protein translation. Thymidylate synthase (TYMS) converts deoxyuridine monophosphate (dUMP) to dTMP in a 5,10-methylene-THF-dependent reaction (not shown). It is important to note that mitochondrial SAM (Mt SAM) is derived from cytosolic SAM (cSAM). Additionally, the Krebs cycle also resides within the mitochondria and provides NADH and FADH2 to the electron transport chain for ATP production. ATP = adenosine triphosphate; c = cytosol; ETC = electron transport chain; FAD = flavin adenine dinucleotide; FADH = reduced flavin adenine dinucleotide; FFA = free fatty acids; HHcy = hyperhomocysteinemia; MS = methionine synthase; Mt = mitochondria; NADH = reduced nicotinamide adenine dinucleotide; T = thymidylate-thymine; U = uracil.” (Hayden, Tyagi, 2022)

I had a reply recently saying nobody understands this (roughly) and my response would be: We learn by studying things that we don’t understand and looking up whatever words we need to look up in order to better understand it.

Here, in this complex graphic (above) – even a First Grader might guess that “Formate” is important. It appears that the nucleus version of the one-carbon cycles will not occur without formate to get it started. SAM is also important – the one-carbon cycle taking place in the cell’s cytoplasm creates the methyl donor cSAM which is converted into mitochondrial mSAM. The nucleus needs the (I don’t know what it is either) “Formate” and cSAM to enter through nuclear pores in order for the one-carbon cycle to be able to take place within the nucleus for DNA methylation needs. Meaning mitochondrial dysfunction of the one-carbon cycle leads to epigenetic changes and lack of DNA methylation in the nucleus of the cell, and dysfunction of the one-carbon cycle in the cytoplasm might precede the mitochondrial dysfunction as the cSAM is needed by the mitochondria and the nucleus. (Hayden, Tyagi, 2022) *They recommend that physicians screen homocysteine levels more often – it is not standardly measured with basic labs.

Formate, heat stress and SMYD3.

Internet answers: Formate is a result of the breakdown of Carbon dioxide, CO2,— and various engineering research approaches have been used to try to reduce CO2 from the air by promoting formate production (in microbes or chemical reactions) – but that is tangentially related and simply was the immediate search results. More to the physiological point – if we want to be able to make formate, we need the gene SMYD3 to be functional and active as it promotes synthesis of formate.

“Conclusions: Our study demonstrates that SMYD3 regulates the activity of the mitochondrial metabolic enzyme MTHFD1L through H3K4me3 histone methylation modification, promotes formate synthesis and induces mitophagy, which inhibits M1 polarization in macrophages.” (Zhu, et al., 2022)

SMYD3 is important in histone methylation, and growth of embryos and cancer tumors, in order to localize it to the nucleus, where we need it for the one carbon cycle and methylation of DNA, Heat Shock Protein 90 (HSP 90) is needed as a nuclear chaperone (~transport protein). “[12, 23, 31]” (Bernard, et al, 2021)

“In summary, SMYD3 is critical for the activation of MAP3K2, a key kinase in the Ras-activated MAP signaling pathway, in both lung and pancreatic cancers. Furthermore, SMYD3 is associated with advanced stage and poor survival in NSCLC, and promotes cell proliferation, invasion, and chemotherapy resistance phenotypes.” (Bernard, et al, 2021)

… ‘miR-3613-3p/MAP3K2/p38/caspase-3 pathway regulates the heat-stress-induced apoptosis of endothelial cells’ (Liu, Liu, Chen, 2021)

“The results revealed that miR-3613-3p expression was reduced in human umbilical vein endothelial cells (HUVECs) following [heat stress] HS, which led to apoptosis. Mechanistically, following HS, a decrease in miR-3613-3p binding to the 3′-untranslated region of MAP3K2 directly upregulated its expression, and the downstream p38 and caspase-3 pathways, thereby leading to apoptosis. Taken together, the results of the present study demonstrated that HS suppressed miR-3613-3p expression, which activated the MAP3K2/p38/caspase-3 pathway, leading to the apoptosis of HUVECs.” (Liu, Liu, Chen, 2021)

Our goal – to not get overheated – avoid heat stress.

Not the same miRNA exactly, but from an interesting paper. “Chen et al. identified two miRNAs (hsa-miR-1307-3p and hsa-miR-3613-5p) that could prevent viral replication by targeting the 3′-UTRs of replication-related SARS-CoV-2 RNA 67.” (Yang, et al., 2022)

Pomegranate and heat stress – nature designed the plant to tolerate heat.

Pomegranate is a sustainable crop because it can tolerate heat, and salty soil and doesn’t need much water. The MAPK pathway is inhibited by pomegranate peel extract, and also by the 9 polyphenols discussed in the post: 1. “microRNA are the real regulators of gene transcription”. – Substack. I am not sure if the MAP3K2 is similarly inhibited but it seems likely.

Postural Orthostatic Tachycardia Syndrome can have an epigenetic cause.

Why is this important? Postural Orthostatic Tachycardia Syndrome is no fun and kind of scary. If you stand up too fast, your blood pressure can no longer shift quickly enough, however that works, and you get dizzy and need to grab something and rest a minute to get the accompanying tachycardia (very rapid heart rate, like it is trying to leap out of your chest almost). Laying down and lifting the knees and feet up helps slow the heart rate. Sitting or at least pausing is necessary or fainting may occur. I did faint once or twice and that is an odd feeling to find yourself on the floor after you come around. See: POTS – Postural Orthostatic Tachycardia Syndrome, can be epigenetic & therefore may be reversible. (substack.com) *Includes the Dystonia section of my Genes Table with more info and a link to my book chapter on the topic (but in computer lingo, the links don’t work).

Many chronic conditions involve epigenetic changes. Sometimes it can be reversed but not always and less likely the longer the condition has lasted. I had POTS-like symptoms for a few months twice and I figured out how to get better. It is not a fun condition and standard treatment usually does not help enough. People become physically disabled as it worsens. You can’t over-exert or stand up too fast or the symptoms of dizziness and racing heart occur.

When you have an open mind, you can learn new things.

Epigenetics – the basics.

Epigenetics – an overview/the opening of an Abstract about a review paper focused on cancer treatment and epigenetics:

“Epigenetics refers to heritable changes that are not encoded in the DNA sequence itself, but play an important role in the control of gene expression.

In mammals, epigenetic mechanisms include changes in

  • DNA methylation,
  • histone modifications and
  • non-coding RNAs.
    • [microRNA are non-coding RNAs (19-23 nucleotides) and there are also longer ones (up to ~100, or a few >/= 200 nucleotides) that are still shorter than an mRNA which is used to transcribe a protein, so it is the full length of the matching DNA from the gene sequence, but only half of the zipper/ladder shape of the double helix.]

Although epigenetic changes are heritable in somatic cells, these modifications are also potentially reversible, which makes them attractive and promising avenues for tailoring cancer preventive and therapeutic strategies. Burgeoning evidence in the last decade has provided unprecedented clues that diet and environmental factors directly influence epigenetic mechanisms in humans. Dietary polyphenols from green tea, turmeric, soybeans, broccoli and others have shown to possess multiple cell-regulatory activities within cancer cells. More recently, we have begun to understand that some of the dietary polyphenols may exert their chemopreventive effects in part by modulating various components of the epigenetic machinery in humans.” (Link, Balaguer, Goel, 2010)

*Bullet points and note added by me. See: Non-coding RNAs: Classification, Biology and Functioning. (Hombach, Kretz, 2010)

Cancer is mitochondrial dysfunction related to cytoplasm dysfunction of the One-Carbon Methylation cycles.

As it turns out, nature really likes the one-carbon methylation cycle and mitochondria seem to be a control center of our cells rather than the nucleus. Cancer is dysfunction of mitochondria which leads to aberrant signaling to the cell nucleus which leads to cancerous like changes in their growth. Experiments have shown though, that when the nucleus of a cancer cell, with the gene changes in place, is transplanted into a healthy cell with healthy mitochondria and cytoplasm, the cell does not become cancerous. However, when a nucleus from a healthy cell is transplanted into a cancer cell that had its nucleus removed, the cell remains cancerous. When cancer cell mitochondria are transplanted into a healthy cell with a normal nucleus – it changes into a cancer cell with cancerous gene changes and out of control growth. The increased growth may be part of more normal pathways used during embryology and child growth. This indicates that cancer is NOT a GENETIC disease. The disease pathology was connected to the diseased cell’s mitochondria, not the diseased cell’s nucleus.

It turns out that mitochondria direct events within the cell and are the controller for signaling the need for apoptosis – put this cell to a merciful death, it is done. But with dysfunctional mitochondria there is no signal presented to kill the cell and it grows out of control or remains dysfunctional but alive – a senescent cell – alive and consuming, but no longer producing functional benefits for the organism or organ.

Cancer is a mitochondrial dysfunction. The one flaw in Dr Seyfried’s treatment plan though, is that such a high fat diet will still promote mitochondrial dysfunction. I would recommend a less stringent ketone diet, at least after some short-term initial phase that is moderate carb and >/= 50% of calories from fats. Use more ketones and some protein, but a diet above 60% fat may in itself cause mitochondrial dysfunction.

https://www.youtube-nocookie.com/embed/KusaU2taxow?rel=0&autoplay=0&showinfo=0&enablejsapi=0

His depressing but helpful message is that also, the chemotherapy, radiation and some of surgical approaches are likely just adding to mitochondrial dysfunction and making the cancer worse. Carbohydrates and glutamates need to be restricted – and that equals sugar, bread, potatoes, pasta, pizza, tomato products, cheese, soy sauce, Worcestershire sauce, barbecue sauce or barbecue, artificial seasonings, ice cream, sweetened beverages, etc – much of the modern diet in other words.

Resources

/Housekeeping – I noticed an older comment suggesting that I provide checklists or more guidance for what to do, regarding my Table 5 – Nutrients depleted by psychiatric medications, which also are nutrients needed by mitochondria, and are risk factors for schizophrenia, Alzheimer’s dementia, or COVID19. I shortened the name of that Table to ‘Nutrients of Concern’.

See:

  • Downloadable Tools in my toolbox – by Jennifer Depew, R.D. (substack.com)
  • My first Substack post is still pertinent – Nrf2 & NF-kB – 2 proteins to know. (substack.com)

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

(Bernard, et al, 2021) Bernard, B.J., Nigam, N., Burkitt, K. et al., (2021). SMYD3: a regulator of epigenetic and signaling pathways in cancer. Clin Epigenet 13(45) https://doi.org/10.1186/s13148-021-01021-9 Available at: https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-021-01021-9 (Accessed: 5 Dec 2022)

(Hayden, Tyagi, 2022) Hayden, M.R., Tyagi, S.C., (2022). Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer’s Disease and Long COVID. Medicina. 58(1):16. https://doi.org/10.3390/medicina58010016 Available at https://www.mdpi.com/1648-9144/58/1/16 (Accessed: 4 Dec 2022) Figure 1: Folate-Mediated One-Carbon Metabolism (FOCM), Figure 2. Compartmentalization of FOCM.

(Hombach, Kretz, 2010) Hombach S, Kretz M. (2016). Non-coding RNAs: Classification, Biology and Functioning. Adv Exp Med Biol. 937:3-17. doi: 10.1007/978-3-319-42059-2_1. PMID: 27573892. Available at: https://pubmed.ncbi.nlm.nih.gov/27573892/ (Accessed: 5 Dec 2022)

(Link, Balaguer, Goel, 2010) Link, A., Balaguer, F., Goel, A., (2010). Cancer Chemoprevention by Dietary Polyphenols: Promising Role for Epigenetics. Biochemical pharmacology. 80:1771-92. 10.1016/j.bcp.2010.06.036. Available at: https://www.researchgate.net/publication/45090894_Cancer_Chemoprevention_by_Dietary_Polyphenols_Promising_Role_for_Epigenetics/citation/download(Accessed: 5 Dec 2022)

(Liu, Liu, Chen, 2021) Liu J, Xu S, Liu S, Chen B. (2021). miR‑3613‑3p/MAP3K2/p38/caspase‑3 pathway regulates the heat‑stress‑induced apoptosis of endothelial cells. Mol Med Rep. Sep;24(3):633. doi: 10.3892/mmr.2021.12272. Epub 2021 Jul 19. PMID: 34278472; PMCID: PMC8280962. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280962/ (Accessed: 5 Dec 2022)

(Yang, et al., 2022) Yang, C.Y., Chen, Y.H., Liu, P.J., Hu, W.C., Lu, K.C., Tsai, K.W., (2022). The emerging role of miRNAs in the pathogenesis of COVID-19: Protective effects of nutraceutical polyphenolic compounds against SARS-CoV-2 infection. Int J Med Sci. Jul 18;19(8):1340-1356. doi: 10.7150/ijms.76168. PMID: 35928726; PMCID: PMC9346380. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9346380/ (Accessed: 5 Dec 2022)

(Zhu, et al., 2022) Zhu, W., Wang, S., Xue, L., Liu, L., Yang, X., Liu, Z., et al., (2022). The SMYD3-MTHFD1L-formate metabolic regulatory axis mediates mitophagy to inhibit M1 polarization in macrophages, International Immunopharmacology, 113(Part A), 2022, 109352, ISSN 1567-5769, https://doi.org/10.1016/j.intimp.2022.109352. https://www.sciencedirect.com/science/article/pii/S1567576922008360

Posted on

Aging biomarker found to be increased in LongCovid, epigenetic changes possible

Evidence of aging, five years on average, was found in survivors of Covid who experienced ongoing illness after an apparent recovery or even only ever having had mild symptoms initially. (1) Other research has found evidence of autoimmune antibodies against certain types of G-protein coupled receptors – need a different post for that.

  • Evidence for Biological Age Acceleration and Telomere 2 Shortening in Covid-19 Survivors. Alessia Mongelli, Carlo Gaetano, Michela Gottardi Zamperla, et al., medRxiv, April 27, 2021, preprint, (1)
  • “The results show a consistent biological age increase in the post-covid population (mean 58,44 DS 14,66 ChronoAge Vs. mean 67,18 DS 10,86 BioAge, P<0,0001), determining a DeltaAge acceleration of 10,45 DS 7,29 years (+5.25 years above range of normality) compared to 3,68 DS 8,17 years for the COVID19-free population (P<0,0001). A significant telomere shortening parallels this finding in the post-COVID19 cohort compared to COVID19-free subjects (post-COVID19 TL: 3,03 DS 2,39 Kb vs. COVID19-free: 10,67 DS 11,69 Kb; P<0,0001).” (1)
  • Additionally, ACE2 expression was decreased in post-COVID19 patients compare to COVID19-free, while DPP-4 did not change. ” (1)

ACE2 receptor expression was expected to be decreased in patients with increased viral load due to the virus destroying the cells with the receptors. Eventually less ACE2 function would be left and patients would exhibit symptoms similar to genetic ACE2 knockout mice – bred to not have ACE 2 receptors in order to see the effect on health. It can provide information about what function something has to see what goes wrong when the animal doesn’t have it.

Also of interest – stopping the virus from entering the ACE2 receptor means that it can’t replicate and go on to infect other cells or people – pomegranate peel may block access: Pomegranate peel – anti-COVID19, may block ACE2 receptor access to the SARS-CoV-2 virus. I ate some pomegranate peel today. *Recipe at the end of this post, more information about pomegranate prep & benefits G13. Pomegranate.

Pomegranate extract reduces inflammation and modulates health and gene transcription.

Pomegranate extract, of the whole fruit or peel is a very potent anti-inflammatory and modulator of health, (6), even epigenetics to some extent – epigenetics effects which genes will be transcribed into proteins by the cell. Pomegranate extract was found to modulate/effect microRNAs which control which mRNA will get transcribed. (2)

“Pomegranate extract intake reversed the surgery-mediated upregulation of various miRNAs and mildly reduced expression of selected miRNAs in tumour tissue compared with normal tissue.” (2)

What is microRNA? — “Noncoding (nc) RNAs also possess a regulatory effect on gene expression. MicroRNAs (miRNAs) are small ncRNAs of 20–22 nt that inhibit gene expression at the posttranscriptional level either by imperfect base-pairing to the mRNA 3′-untranslated regions to repress protein synthesis, or by affecting mRNA stability (reviewed in [23]).” (2)

What is mRNA? — “Messenger RNA (mRNA) molecules carry the coding sequences for protein synthesis and are called transcripts;” (3) Messenger RNA is copied from the double helix strands of DNA that make a gene. The messenger RNA is a single helix – one ladder leg instead of both sides of the spiraling ladder with nucleotide steps, or one side of a zipper.

What is epigenetics? — “The term ‘epigenetics’ refers to modifications in gene expression caused by heritable, but potentially reversible, changes in DNA methylation and chromatin structure. Major epigenetic mechanisms include DNA hyper- and hypomethylation [11], remodelling of the chromatin, modification of histones by histone acetylation and methylation (among others), and noncoding RNAs [12].” (2)

What are methyl donors? — Folate in the bioactive methylated form and methylated B12 are both helpful for providing the methyl groups needed for DNA methylation. The small chemical group added onto genes is like turning the light switch off, that gene is no longer in the ready to be transcribed mode. Choline is another methyl donor in the B vitamin group. See: Methyl Donors & BPA.

EGCG found in Green tea & Pomegranate Peel may protect length of Telomeres.

Pomegranate peel is also a source of EGCG (more commonly associated with green tea) which has been found protective of telomere length, by inhibiting a telomerase enzyme.

“Epigallocatechin-3-gallate, a major component of green tea polyphenols, downregulated expression of human telomerase reverse transcriptase (hTERT), a major enzyme determining telomere stability, through causing promoter hypomethylation and histone deacetylations, thereby inhibiting proliferation of breast cancer cells [12].” (7)

Polyphenols, alkaloids, triterpenes, and xanthones may be plant nutrients that help inhibit the overactivity of the telomerase enzyme seen in some types of cancer cells. (8) EGCG is a polyphenol. Alkaloids include “morphine, strychnine, atropine, colchicine, ephedrine, quinine, and nicotine.” (11) Triterpenes include sterols (such as vit. D group, 12) and carotenoids (vit A). (9) xanthones are found in the Garcinia, mangosteen fruit. (10) Telomeres are a section of non protein encoding DNA at the end of genes. Telomeres get shorter as we age and longer ones indicate younger metabolic age. Excessive lengthening of telomeres can occur in cancer and that isn’t good either.

The really good news about epigenetic changes – they can be changed back.

“In contrast to irreversible genetic alterations (mutations, deletions, etc.), genes silenced by epigenetic modifications are still intact and can be reactivated [13,14].” (2)

Many genes are turned on or off with the change from night to day/day to night. We do more active energy using work during the day, which produces waste chemicals, and more growth and repair, clean up, at night while we sleep. It is very unhealthy to chronically miss sleep.

Sunlight in the day & blackout curtains at night help immune function with melatonin & sunshine vitamins.

Sunlight in the morning or at some point in the awake hours of the day also helps health.

“People have a feeling of wellbeing when exposed to sunlight. This may be due to the fact that keratinocytes produce β-endorphin when exposed to UV radiation.67 ” (12)

A full spectrum lamp with UVB capability for a half hour of artificial “sun” during winter months or for night shift workers may be more beneficial for health, and mood, than a vitamin D2/D3 supplement. Our bodies make other forms of the vitamin D group of sterols, some water soluble, and other forms of vitamin A are also made. (12, 13)

“Bright light treatment requires a minimum of 2,500 lux to be effective, & the brightness recommended by researchers & clinicians for most people is 10,000 lux – an amount significantly higher than standard indoor lighting.” (14) This reference is recommending no UV in the light treatment, however for the vitamin D and A chemistry UVB is needed and UVA may also have some role in health in moderation.

Seasonal Affective Disorder (SAD) lamps may not provide the UVB, and the UVB intense ones are only meant for 30 minute use or less per day, as sunburn possible, so that type of light wouldn’t treat the SAD problem in the same way as the no UVB lights. (13, 15) The 10,000 lux lamps may be helping patients with Seasonal Affective Disorder (14) by increased beta-endorphins. Serotonin increase is involved in the benefit of Bright Light Therapy (BLT) which was found to be better than placebo in a metareview. (16) Bright Light Therapy was found to reduce cerebral monoamine oxidase A (MAO-A) levels which have a seasonal decrease in healthy controls compared to participants with SAD. Serotonin receptors and transport proteins may also be affected by the light treatment. (17)

Black out curtains at night and covering all little alarm clock lights and other device lights helps our body switch into night-time biology of clean-up and repair. Melatonin is also made at night and lights can reduce the amount that is made. It helps immune function and seems helpful against COVID-19. Melatonin produced in the lungs prevents infection by novel coronavirus. (18)

Lack of niacin, which is needed in increased amounts during infection or inflammation, would lead to overuse of tryptophan instead. Lack of tryptophan would lead to a lack of serotonin and melatonin, both of which are made from tryptophan. (19)

We may need a healthy gut microbiome, to have overall health.

The microbes in our intestines may have a larger role in health than we realized because they also impact our epigenetics – we want our good guys to be helping us then.

“Recent research has indicated that the gut microbiota and gut microbial metabolites might be important mediators of the diet–epigenome interaction (previously reviewed in [29–31]).” (2)

Obesity has been found to be related frequently to less beneficial microbiome species. (4) Anxiety can also be linked to microbiome species. (5) “Animal models strongly suggest a role for the gut microbiome in anxiety- and trauma-related disorders. The microbiota–gut–brain (MGB) axis sits at the epicenter of this new approach to mental health. The microbiome plays an important role in the programming of the hypothalamic–pituitary–adrenal (HPA) axis early in life, and stress reactivity over the life span.” (5)

More information about POTS & epigenetic changes:

I go into more detail about epigenetic changes, methyl donors and Postural Orthostatic Tachycardia Syndrome (POTS) – a problem that has been occurring for some Covid survivors and a problem I’ve had symptoms of twice and got better from twice – See: Epigenetic changes may also be involved in Covid19 or LongCovid. I prefer being healthy to being unhealthy and I’m willing to work to get better when I can.

Seasoned Peas and Pistachios, with Pomegranate peel.

Peas with pistachios, with cumin and coriander and a little pomegranate peel (inner pith)..

*Pound of frozen Peas, boil for a few minutes with a cup of Pistachios in water to cover the food – then pour off the water. It may contain oxalates from the pistachios. Add a 1/4 cup of fresh water to the drained food along with a half teaspoon of Cumin, Coriander and Gumbo file; one tablespoon powdered or minced dehydrated Pomegranate Peel (inner pith); and simmer with the peas & pistachios for a minute or two to set the Gumbo file thickener and mix the flavors. Serve the peas hot or cold with a little Apple Cider Vinegar and Salt to taste. Makes about four 3/4 cup servings.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

  1. Alessia Mongelli, Carlo Gaetano, Michela Gottardi Zamperla, et al., Evidence for Biological Age Acceleration and Telomere 2 Shortening in Covid-19 Survivors. medRxiv, April 27, 2021, preprint, https://www.medrxiv.org/content/10.1101/2021.04.23.21255973v1
  2. Clarissa Gerhauser, Impact of dietary gut microbial metabolites on the epigenome. Royal Society, 23 April 2018, https://doi.org/10.1098/rstb.2017.0359 https://royalsocietypublishing.org/doi/10.1098/rstb.2017.0359
  3. Ribosomes, Transcription, and Translation, nature.com/scitable https://www.nature.com/scitable/topicpage/ribosomes-transcription-and-translation-14120660/
  4. Davis CD. The Gut Microbiome and Its Role in Obesity. Nutr Today. 2016;51(4):167-174. doi:10.1097/NT.0000000000000167 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082693/
  5. Stefanie Malan-Muller, Mireia Valles-Colomer, Jeroen Raes, et al., The Gut Microbiome and Mental Health: Implications for Anxiety- and Trauma-Related Disorders. OMICS J of Integ Biology, Vol 22, 2, 2018, Mary Ann Liebert, Inc. DOI: 10.1089/omi.2017.007 https://www.liebertpub.com/doi/pdfplus/10.1089/omi.2017.0077
  6. Ceci C, Lacal PM, Tentori L, De Martino MG, Miano R, Graziani G. Experimental Evidence of the Antitumor, Antimetastatic and Antiangiogenic Activity of Ellagic Acid. Nutrients. 2018;10(11):1756. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266224/Published 2018 Nov 14. doi:10.3390/nu10111756
  7. Yan Bian, Juntong Wei, Changsheng Zhao and Guorong Li, Natural Polyphenols Targeting Senescence: A Novel Prevention and Therapy Strategy for Cancer. Int J Mol Sci. 2020, 21, 684; https://www.dropbox.com/s/wckq66cgye3yjr4/ijms-21-00684-v3.pdf?dl=0doi:10.3390/ijms21020684
  8. Kumar Ganesan ID and Baojun Xu, Telomerase Inhibitors from Natural Products and Their Anticancer Potential. Int. J. Mol. Sci. 2018, 19, 13; doi:10.3390/ijms19010013 https://www.dropbox.com/s/xjhguj3dnbop6h2/ijms-19-00013.pdf?dl=0
  9. Triterpenes, sciencedirect.com, https://www.sciencedirect.com/topics/chemistry/triterpene
  10. Xanthones, sciencedirect.com, https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/xanthone
  11. Alkaloids, sciencedirect.com, https://www.sciencedirect.com/topics/food-science/alkaloid
  12. Wacker M, Holick MF. Sunlight and Vitamin D: A global perspective for health. Dermatoendocrinol. 2013;5(1):51-108. doi:10.4161/derm.24494 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897598/
  13. CK Eternity, The Truth about Vitamin D Metabolism, Mar 12, 2021, Patreon.com, https://www.patreon.com/posts/truth-about-d-48683534
  14. Bright Light Treatment Research. sunbox.com, https://www.sunbox.com/research/bright-light-treatment-research/
  15. Ezvid Wiki, The 6 Best Vitamin D Lights – 2019, Nov 28, 2018, youtube.com, https://www.youtube.com/watch?v=iqk9hzYC5Mc&feature=youtu.be
  16. Pjrek E, Friedrich M, -E, Cambioli L, Dold M, Jäger F, Komorowski A, Lanzenberger R, Kasper S, Winkler D: The Efficacy of Light Therapy in the Treatment of Seasonal Affective Disorder: A Meta-Analysis of Randomized Controlled Trials. Psychother Psychosom 2020;89:17-24. doi: 10.1159/000502891 https://www.karger.com/Article/Abstract/502891
  17. Spies, M., James, G.M., Vraka, C. et al. Brain monoamine oxidase A in seasonal affective disorder and treatment with bright light therapy. Transl Psychiatry8, 198 (2018). https://doi.org/10.1038/s41398-018-0227-2 https://www.nature.com/articles/s41398-018-0227-2
  18. Elton Alisson, Melatonin produced in the lungs prevents infection by novel coronavirus. Agência FAPESP, Jan 27, 2021 https://www.eurekalert.org/pub_releases/2021-01/fda-mpi012721.php
  19. Dmitry Kats, Tweets & images regarding tryptophan, melatonin, and niacin. “Yes, and melatonin is depleting as a result of tryptophan depleting due to inflammation, and only exclusively sufficient niacin supply can flush this inflammation out to then accordingly restore auxiliary biochem and health” “Funny how melatonin is being pushed through publications in relation to #COVID19, whilst they purposefully censor or “ignore” the inflammatory biochemical mechanism that causes this melatonin deficiency & how sufficient niacin supply nips the inflammation in the bud to restore it” https://twitter.com/NiacinIsHealth/status/1354624867300241408?s=20
Posted on

Epigenetic changes may also be involved in Covid19 or LongCovid

Epigenetic changes may be involved in Covid19 and LongCovid, which might be able to be changed back with the addition of plenty of methyl donor vitamins. People with methylation genetic alleles would be more at risk for epigenetic changes to DNA or actin protein filaments. Actin are semi flexible proteins in a double helix shape which support the fluid and organelles inside of cells and around cells and organs of our bodies. Actin also is involved in guiding the work of DNA replication and growth and development of cells or infants.

Methylation is the addition of a methyl group – one carbon atom and three hydrogen atoms, to genes, or actin filaments. A methylated gene is not active for encoding proteins while a demethylated gene is available to be transcribed into a messenger mRNA to be made into a matching protein. Actin filaments are a double helix shape like DNA but do other functions throughout our body. Some have methyl groups also that seem to be essential for proper function of the actin protein whether in muscle contraction or in guiding chemicals within cells to make DNA or do other work. Actin filaments add structure to the jelly like fluid around and in cells and may tether chemicals in place for chemical reactions or guide cellular organization during growth and development.

Actin may be involved with energy fields of our body along with microtubules also, but that is not discussed in greater detail in this post (more information about quantum energy fields and actin is included in Cracking Nature’s Code (2019) (1), and in several posts on another site of mine first in the series, 2nd, 3rd, 4th).

Viral infection and epigenetic changes with a focus on Postural Orthostatic Tachycardia Syndrome and possible dietary and lifestyle changes that may help reverse epigenetic changes is the focus of this post – which got long. It is also available as a section of this document that includes the series on Mast Cells and Histamine. Current standard of treatment for patients with POTS symptoms may leave them unwell for years – a few get better more rapidly. I got better on my own within a few months – twice. More about possible strategies for improvement of epigenetic changes will be included later in the post. More about the epigenetics involved in POTS is included in the Genetics/Epigenetics chapter of my book draft which is available on a platform where you can get an e-copy early (minimum price Free, Leanpub/Tipping The Clock Toward Health) and then be informed of updates with an email subscription.

Viral infection can cause Epigenetic changes.

“Bacterial (Pacis et al., 2015, 2) and viral infection (Lichinchi et al., 2016, 3) directly impact methylation patterns, most likely orchestrated by actin since it is universally hi-jacked in viral infectivity (Cudmore et al. 1997, 4; Ohkawa and Volkman, 1999, 5; Lu et al., 2004, 6; Marek et al., 2011, 7).”

page 34, JB Head, PhD, Cracking Nature’s Code (2019) (1)

I found I have methylation gene alleles in a genetic screening (post: Methylation Cycle Defects – in me – genetic screening “for research purposes only”). Since finding out I stopped taking standard supplements of B12 and folic acid because they are not methylated, not bioactive. I take methyl B12 & methyl folate supplements now. Postural Orthostatic Tachycardia Syndrome (POTS) (9) has been a problem for me in past years a couple times and I got better. Symptoms include a rapid heart rate, tachycardia, and feeling faint or blacking out, especially when getting up quickly from a seated or laying down position to standing. (9) I have heard anecdotal reports of it being a symptom for some LongCovid survivors who had never had the problem before.

To slow the rapid heart rate during an episode I found it helpful to stop and sit or lay down with my feet above my heart if possible and just wait a couple minutes for the rapid heart rate to slow again. Continuing to exercise would make the rapid heart rate worse. Preventing the faintness upon rapidly getting up required trying to remember to slow down and have a support ready to hold if I felt wobbly. I did faint once, odd to find yourself on the floor unexpectedly.

POTS has been found to potentially involve a genetic difference in the norepinephrine transporter gene (SLC6A2) sequence and it can also be an epigenetic problem with links to excess formaldehyde. (9) Formaldehyde can donate methyl groups to DNA that normally would be unmethylated – active. (10) Methylation of DNA is a little like a on/off switch for genes, or the cap on bottle – add the methyl groups and the DNA gene is inactive.

“Formaldehyde as a methyl donor for the methylation of DNA, RNA, and histone acts as an epigenetic factor participating in the reversible and dynamic methylation. DNA demethylation elicits formaldehyde generation in the dividing cells and post-mitotic neurons.” (10) Memory formation involves methylation of DNA and cognitive impairment in older adults is associated with increased internal formaldehyde levels (self-made) and demethylation of DNA. Use of nutrients to remove formaldehyde helped improve memory in an animal based study. (10)

Formaldehyde can be prevalent in secondhand or thirdhand smoke in enclosed rooms, or smog, or we make our own during normal metabolism, and physical or emotional stress conditions may cause an increase, as well as the level potentially increasing in older adults. (11) Elevated levels of formaldehyde within cells causes more breakdown of sugar for energy and increased removal of an antioxidant out of the brain cells, which may increase risk for cognitive damage. “As excess formaldehyde accelerates glycolysis and glutathione export in neural cells, formaldehyde‐induced alterations in brain metabolism and oxidative stress may contribute to the pathological progression of neurodegenerative disorders.” (11)

Formaldehyde is very reactive and can use the methyl group to form links between protein groups or parts that wouldn’t normally be linked – like bungee cords holding parts together in places that would be separate in normal function. (11) Formaldehyde is used with tissue samples to preserve material for viewing under a microscope. Studies of the effect of formaldehyde on the actin protein of live cells that were low on blood sugar found that modifications to the protein did occur – the authors suggest any prior research on the actin protein in formaldehyde treated samples may be inaccurate. (12) Take home point – formaldehyde is not good for our brain cells and may effect the protein of our brain cytoskeleton structure. (12) Protein tangles in brain cells are associated with dementia and autism.

What is a cytoskeleton? We are mostly water, so how do we walk around? With a balance in tension between string like ligaments and muscles and rod like bones of our skeleton. Within the cellular environment, inside and outside the cell membrane – the tent wall, there are rod like microtubules and string like actin protein that is more flexible, it can change shape but isn’t stretchy as much as structurally able to modify in shape. Actin is a double helix, two spirals like DNA except without the ladder like steps joining the two lengths of protein. When force is applied the double helix can get a little longer or shorter as the coils compress or lengthen slightly – tensile strength – and the protein gets stiffer from a side to side direction – torsion – and is less flexible along the length, less able to bend sideways. (13)

The actin protein may act as torsion sensors – is the environment changing in pressure around that section of the protein length – from increased fluid or gas? How full is the balloon like membrane? (14) Channels in a membrane will open and start to leak rather than letting the membrane burst like an overfull balloon. This may seem like a silly discussion – however it is your brain and organs – leaking is better than bursting. Leaking membranes will release fluid and some types of chemicals while a bursting open, as when viral replication is complete and the virus exit a cell, the membrane bursts and all the remaining chemicals in the cell flood into the surrounding cytoskeleton and can cause inflammatory damage to surrounding cells.

These flexible yet firm cytoskeleton actin filaments also may act like guidelines for directing traffic or tethering organelles in place for activity such as replication of DNA during cell division (one cell doubles its DNA and then divides into two cells). Too much of the proteins within a cell nucleus will prevent DNA replication rather than guiding it. (15) Actin is also involved in muscle fiber motion. The double helix structure can also be methylated with methyl groups doing an unknown but critical function. Loss of methylation of actin in one location is associated with cancer and autism spectrum disorders, (16), loss of it in another location along the protein chain is associated with muscle changes that cause female animals to have delivery problems and fewer babies. (17, 18)

So actin is important stringy protein that effects muscle power, cell division, and the brain – and formaldehyde can cause demethylation of DNA, likely it can cause demethylation of actin also which may lead to autism spectrum disorders, cancer, and muscle problems that can affect a healthy delivery of infants (in an animal study). The visual – we want our jelly like insides to have a strong yet flexible tent membrane, tent poles (microtubules), and tie downs (actin) – without having so many tie downs it starts looking like a haunted house full of cobwebs. The amyloid beta protein associated with Alzheimer’s dementia and autism may be protective against a low level infection (post: Magnesium might help protect against beta amyloid placques) but also may increase changes in actin stress fibers (24) and an excess seems to add to chronic inflammatory damage over time.

How do we achieve this? Healthy actin?

It may help promote appropriate methylation of DNA and actin to have adequate antioxidants and methyl donor nutrients in our diet, to reduce oxidative stress chemicals and provide adequate methylation to DNA and actin. Avoiding excessive physical and emotional stress may also be an important strategy, so we aren’t embalming ourselves with self produced formaldehyde (the mummy in the haunted house being our own brain).

We also want to avoid formaldehyde in our environment, which would include improving air quality, especially during sleep hours when our body is focused on detoxification of the brain. Parkinson’s Disease is another chronic condition that may involve epigenetic changes and reducing formaldehyde exposure may be protective. More information is in this post with a link to a longer post about formaldehyde sources: The Cholinergic System

Increasing methyl donor vitamin rich foods and/or supplements should focus on the methylated form if unsure whether there is a genetic allele problem causing lack of methylation.

“Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl group can directly be delivered by dietary methyl donors, including methionine, folate, betaine, and choline.” … “Studies that simulated methyl-deficient diets reported disturbances in energy metabolism and protein synthesis in the liver, fatty liver, or muscle disorders.” … “Hypomethylation has a wide spectrum of effects that include genetic, epigenetic, and metabolic alterations.” (8)

Gastrointestinal problems have been found to be common among patients with Postural Orthostatic Tachycardia Syndrome (POTS) with malfunction or slowing, dysmotility, of the smooth muscle lining of the intestinal tract. “Case study 1: A 20-year-old woman presented to clinic for further evaluation of a several year history of fullness and epigastric discomfort associated with eating and irregular bowel habits. Her weight was stable. She also described frequent migraine headaches, episodic palpitations and lightheadedness with progressively increasing episodes of syncope. A systems review was notable for profound fatigue, dry eyes and mouth and intermittent flushing and pruritus.” (19) The patient’s symptoms include many in common with Mast Cell Activation Syndrome, however testing for mast cell activation was normal. Patients whose symptoms followed a viral infection tend to get better more often than patients with a family history of POTS. (19)  

“A number of chronic conditions are frequently seen in patients with POTS and contribute to symptom burden and reduced quality of life. Common comorbidities include chronic fatigue syndrome, fibromyalgia, interstitial cystitis, and migraine headaches. Other unique conditions that seem to occur with increased frequency in POTS are autoimmunity, the hypermobile form of Ehlers-Danlos syndrome (HM-EDS), and mast cell activation disorder (MCAD).” (19)  

“Unlike mastocytosis, idiopathic mast cell activation [MCAD] occurs in the absence of mast cell proliferation and with episodic accumulation of mast cell mediators in the plasma or urine, usually present when symptomatic. Patients with MCAD typically present with episodic “attacks” of flushing, urticaria and pruritus accompanied by lightheadedness, dizziness, dyspnea, nausea, headache, diarrhea, and/or syncope; symptoms representative of the hyperadrenergic type of POTS with biochemical evidence of MCAD (20).” (19)

The patient in case study 2 had ongoing nausea, vomiting, abdominal pain, and weight loss continuing for years following a viral infection. She was found to have deficiency in iron, zinc, and vitamin B12 and gastroparesis (slow or little intestinal muscle action). Intravenous iron and B12 were provided and an oral zinc supplement. Nutrient levels improved however the GI symptoms and weight loss continued and the patient was given tube feedings which improved weight, however some intolerance to the tube feedings continued and abdominal pain persisted. (19)  

If demethylation of actin protein in the muscle tissue of the intestinal wall was a problem for the patient in case study 2, then it may have been a factor in the gastroparesis. Genetic screening for methylation defects is not mentioned. Supplements of B12 are often an unmethylated form, cyanocobalamin, and which include cyanide. (21) In a study of 12 patients by Huang et al, (22): “Disturbances in GI motility were found to involve not only the stomach, but also multiple segments of the gut spanning the esophagus to the anus.” (19) The commonly used treatments for GI symptoms associated with POTS (see Table 5) do not include nutrients and do include proton pump inhibitors, (19),  a medication that takes the place of magnesium as a calcium channel blocker, and which may lead to worse magnesium deficiency for some people, a genetic difference may be involved. See post: Original Prilosec Warning, edited.

Small intestinal bacterial overgrowth (SIBO) may occur along with GI problems and lead to fat and carbohydrate digestion and absorption problems and bloating from excessive bacterial growth. Changes in diet due to the discomfort are common in patients with POTS and these more severe GI symptoms and which may lead to deficiencies in fat soluble vitamins A, D, E and K. Megaloblastic anemia may result from deficiencies in iron, folate and vitamin B12. (19) Sulfate deficiency may be an underlying factor (23) and providing Epsom salt soaks of the lower legs and feet, or in a bath one to two times a week might help by providing a topically absorbed form of magnesium and sulfate. See post: To have optimal Magnesium needs Protein and Phospholipids too.

Zinc is also involved in DNA methylation and deficiency of the trace mineral can lead to epigenetic changes and gene transcription problems. Zinc is needed along with actin and other proteins to tell the cell nucleus and cell which genes to make into mRNA to be encoded into a protein. “Accumulating evidence has demonstrated that several key enzymes and zinc finger proteins with zinc atom(s) in the reactive center and binding site play important roles in DNA methylation and histone modifications. Therefore, zinc deficiency may disrupt the functions of these enzymes and proteins and result in epigenetic dysregulation. Furthermore, zinc deficiency may enhance inflammatory response and subsequently alter DNA methylation status of the genes involved in inflammation.” (20) Also see posts: Zinc – big news, CoV and other illness related, and Zinc, cancer, and bitter taste receptors.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

  1. JB Head, PhD, Cracking Nature’s Code: The Potential Answer to Everything. (Balboa Press, Bloomington, IN, 2019) https://www.balboapress.com/en/bookstore/bookdetails/792280-cracking-natures-code
  2. Pacis A, Tailleux L, Morin AM, et al., Bacterial infection remodels the DNA methylation landscape of human dendritic cells. Genome Res 2015. 25: 1801-1811 https://doi.org/10.1101/gr.192005.115 https://genome.cshlp.org/content/25/12/1801
  3. Lichinchi G, Zhao BS, Wu Y, et al. Dynamics of Human and Viral RNA Methylation during Zika Virus Infection. Cell Host Microbe. 2016;20(5):666-673. doi:10.1016/j.chom.2016.10.002 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155635/
  4. Cudmore S, Reckmann I, Way M. (1997). Viral manipulations of the actin cytoskeleton. Trends in microbiology. 5. 142-8. 10.1016/S0966-842X(97)01011-1. https://www.researchgate.net/publication/14077627_Viral_manipulations_of_the_actin_cytoskeleton
  5. Ohkawa T, Volkman LE, Nuclear F-Actin Is Required for AcMNPV Nucleocapsid Morphogenesis, Virology, Vol 264, Issue 1, 1999, Pages 1-4, ISSN 0042-6822, https://doi.org/10.1006/viro.1999.0008. https://www.sciencedirect.com/science/article/pii/S0042682299900089
  6. Lu, S., Ge, G. & Qi, Y. Ha-VP39 binding to actin and the influence of F-actin on assembly of progeny virions. Arch Virol149, 2187–2198 (2004). https://doi.org/10.1007/s00705-004-0361-4 https://link.springer.com/article/10.1007/s00705-004-0361-4
  7. Marek M, Merten OW, Galibert L, Vlak JM, van Oers MM. Baculovirus VP80 protein and the F-actin cytoskeleton interact and connect the viral replication factory with the nuclear periphery. J Virol. 2011;85(11):5350-5362. doi:10.1128/JVI.00035-11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094977/
  8. Obeid R. The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway. Nutrients. 2013;5(9):3481-3495. Published 2013 Sep 9. doi:10.3390/nu5093481 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798916/
  9. Richard Bayles, Harikrishnan KN, Elisabeth Lambert, et al., Epigenetic Modification of the Norepinephrine Transporter Gene in Postural Tachycardia Syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32:1910–1916 https://doi.org/10.1161/ATVBAHA.111.244343 https://www.ahajournals.org/doi/full/10.1161/atvbaha.111.244343
  10. Su, Tao & He, Rong-Qiao. (2017). Formaldehyde Playing a Role in (De)methylation for Memory. 10.1007/978-94-024-1177-5_3. https://www.researchgate.net/publication/320523716_Formaldehyde_Playing_a_Role_in_Demethylation_for_Memory
  11. Ketki Tulpule Ralf Dringen, Formaldehyde in brain: an overlooked player in neurodegeneration?, J. Neurochem. (2013) 127, 7– 21 https://onlinelibrary.wiley.com/doi/10.1111/jnc.12356
  12. Vasicova P, Rinnerthaler M, Haskova D, et al. Formaldehyde fixation is detrimental to actin cables in glucose-depleted S. cerevisiae cells. Microb Cell. 2016;3(5):206-214. Published 2016 Apr 12. doi:10.15698/mic2016.05.499 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349148/
  13. Effect of tensile force on the mechanical behavior of actin filaments. J Biomechanics (2011), 44(9): 1776-1781, 2011-06-03 , https://repository.kulib.kyoto-u.ac.jp/dspace/handle/2433/152437 https://core.ac.uk/download/pdf/39280196.pdf
  14. Hayakawa K, Tatsumi H, Sokabe M. Actin filaments function as a tension sensor by tension-dependent binding of cofilin to the filament. J Cell Biol. 2011;195(5):721-727. doi:10.1083/jcb.201102039 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257564/
  15. Hu, X., Liu, Z.Z., Chen, X. et al. MKL1-actin pathway restricts chromatin accessibility and prevents mature pluripotency activation. Nat Commun10, 1695 (2019). https://doi.org/10.1038/s41467-019-09636-6 https://www.nature.com/articles/s41467-019-09636-6
  16. Seervai RNH, Jangid RK, Karki M, et al., The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase. Science Advances, 02 OCT 2020 : EABB7854 SETD2 regulates actin dynamics and cell migration via methylation of actin at Lys68 in a cellular complex containing Huntingtin. https://advances.sciencemag.org/content/6/40/eabb7854? “Disruption of the SETD2-HTT-HIP1R axis inhibits actin methylation, causes defects in actin polymerization, and impairs cell migration. Together, these data identify SETD2 as a previously unknown HTT effector regulating methylation and polymerization of actin filaments and provide new avenues for understanding how defects in SETD2 and HTT drive disease via aberrant cytoskeletal methylation.“… “Loss of SETD2 and the H3K36me3 chromatin mark is embryonic lethal in Drosophila (7) and mice (8), and SETD2 defects have been linked to several diseases, including cancer (9–11) and autism spectrum disorder (12–14).”
  17. Wilkinson, A.W., Diep, J., Dai, S. et al. SETD3 is an actin histidine methyltransferase that prevents primary dystocia. Nature 565, 372–376 (2019). https://doi.org/10.1038/s41586-018-0821-8, https://www.nature.com/articles/s41586-018-0821-8 lack of the methylation at histidine 73 seems to interfere with muscles and causes the genetically different animals to have fewer babies due to maternal delivery problems. Graphic from the article shows a CH3 methyl group being added to an actin filament at Histidine 73: https://twitter.com/anandb4/status/1073255833813671937?s=20
  18. Kwiatkowski S, Seliga AK, Veiga-da-Cunha M, et al., SETD3 protein is the actin-specific histidine N-methyltransferase. bioRxiv 266882; doi: https://doi.org/10.1101/266882Now published in eLife doi: 10.7554/elife.37921 https://www.biorxiv.org/content/10.1101/266882v1?platform=hootsuite “Finally, Setd3-deficient HAP1 cells were devoid of methylated H73 in β-actin and exhibited phenotypic changes, including a decrease in F-actin content and an increased glycolytic activity. “
  19. DiBaise JK, Lunsford TN, Harris LA, Nutrition Issues in Gastroenterology, Series #187: The POTS (Postural Tachycardia Syndrome) Epidemic: Hydration and Nutrition Issues. June 2019, Practical Gastro, Vol XLIII, Issue 6 https://practicalgastro.com/2019/10/14/the-pots-postural-tachycardia-syndrome-epidemic-hydration-and-nutrition-issues/
  20. Gu H.F., Zhang X. (2017) Zinc Deficiency and Epigenetics. In: Preedy V., Patel V. (eds) Handbook of Famine, Starvation, and Nutrient Deprivation. Springer, Cham. https://doi.org/10.1007/978-3-319-40007-5_80-1 https://link.springer.com/referenceworkentry/10.1007%2F978-3-319-40007-5_80-1
  21. Dody Chiropractic, Why Do Vitamin B12 Supplements Contain Cyanide?, dodychiro.com,  https://www.dodychiro.com/why-do-vitamin-b12-supplements-contain-cyanide/
  22. Huang RJ, Chun CL, Friday K, et al. Manometric abnormalities in the postural orthostatic tachycardia syndrome: a case series. Dig Dis Sci 2013;58:3207-3211 https://pubmed.ncbi.nlm.nih.gov/24068608/
  23. Elliot Overton, Sulfate IV: Chronic SIBO/Gut Dysbiosis As A Protective Adaptation To Supply Sulfate. July 21, 2018, Eonutrition.co.uk, https://www.eonutrition.co.uk/post/sulfate-iv-chronic-sibo-gut-dysbiosis-as-a-protective-adaptation-to-supply-sulfate 
  24. Song C, Perides G, Wang D, Liu YF. beta-Amyloid peptide induces formation of actin stress fibers through p38 mitogen-activated protein kinase. J Neurochem. 2002 Nov;83(4):828-36. doi: 10.1046/j.1471-4159.2002.01182.x. PMID: 12421354. https://pubmed.ncbi.nlm.nih.gov/12421354/
  25. Frederic Dorandeu, Guilhem Calas, Gregory Dal Bo, Raafat Fares, Chapter 36 – Models of Chemically-Induced Acute Seizures and Epilepsy: Toxic Compounds and Drugs of Addiction, Editor(s): Asla Pitkänen, Paul S. Buckmaster, Aristea S. Galanopoulou, Solomon L. Moshé, Models of Seizures and Epilepsy (Second Edition),Academic Press, 2017, Pages 529-551, ISBN 9780128040669, https://doi.org/10.1016/B978-0-12-804066-9.00037-7. https://www.sciencedirect.com/science/article/pii/B9780128040669000377 “Alterations of the neuronal cytoskeleton, and more precisely disruption of actin dynamics, seem then to contribute to changes in brain excitability, but the mechanisms leading to these changes remain still unresolved (Spence and Soderling, 2015).” Excerpt viewable in F-actin, ScienceDirect, https://www.sciencedirect.com/topics/neuroscience/f-actin