microRNA, elevated homocysteine and is there a role for excess Retinoic Acid?

Yes, there may be. However simply having a high fat or high saturated fat diet may be factors, or low intakes of choline, methyl folate and methyl B12. Lack of riboflavin might be a factor also.

I gave the solution - plant polyphenols - in the last post: microRNA are the real regulators of gene transcription. (substack.com) and a link to another SubStack about some of the chronic illness that has been linked to microRNA changes - but I didn’t get into The Problem.

My usual blogging format tends to be - set up the problem, show the underlying functional issues, and then show how simply providing the body the needed nutrients in the necessary amounts, (which may be elevated from average), can help, or lifestyle or diet balance changes. My solutions are frequently different than standard medical industry interventions, which makes me feel it necessary to show the mechanism of action that may be the underlying cause before providing the Try-This ideas - but that may bore many readers. Either they don’t care, and/or it is too complex even with my attempts to simplify it, or I have made it overly simplified for the science readers who do know about the topic and could bring new solutions to their own patients - if they listened and heard me. Can’t win for losing, try anyway! - one of my mottos for life. Without trying there is neither a win nor a loss.

With that said - elevated homocysteine is a very complex topic, buckle up for safety, we are going on a ride. *This is just one section of one Table, from my pomegranate paper. It did outgrow the format of the other sections. The Table is about Gene alleles that can be involved in histamine excess, Retinoid Toxicity, or schizophrenia and I provide some of my own gene polymorphisms as an example case. I like health. I have been a chronically not quite healthy person most of my life and figuring out how to improve my health has been complex and wouldn’t have been possible without reading the medical research for myself. Far too often, almost exclusively, very helpful findings end with a tagline about how this information might help to create a new drug . . . or it could simply be used to educate patients about how they could restore normal function. However, that would not lead to monthly prescription purchases or office visits at least every 3-6 months.

Take home points about elevated homocysteine:

• Standard treatment is B6, B12 and folic acid supplementation to help promote metabolism of homocysteine and the effectiveness is inconsistent. *Please at least use or recommend methyl folate and methylhydroxy cobalamin.

• Methionine levels may be elevated, normal or low with elevated homocysteine dependent on the type of dysfunctional alleles. *Figuring out which category an individual falls into WOULD be helpful because methionine could be reduced or increased in the diet or with use of supplements and it is needed too - deficiency would be a health problem. It is often the source of cysteine for glutathione production, as methionine is converted into homocysteine which is converted into cysteine which is used to make glutathione in the One Carbon interconnected methylation cycles. See: (Weber Hoss, Poloni, Blom, Doederlein Schwartz, 2019; Fig. 1) or (Obeid, 2103, Fig. 1) or graphic below by (Hayden, Tyagi, 2022).

• The most common reason for hyperhomocysteinemia are gene differences in the metabolic pathways of the One Carbon Cycle but diet may also be a factor. Excess methionine intake (red meat, dairy, protein supplements) can be a causal factor of elevated homocysteine. This article includes gene alleles of the author, used as an example of a heterogenic risk for elevated homocysteine (and other conditions are included in other sections that didn’t quite this long).

• Hyperhomocysteinemia is also associated with alcoholism and retinal conditions - however, it itself, seems to have some protective factors as elevated homocysteine can promote Nrf2, which then helps reduce the elevation of oxidative stress that is associated with excess homocysteine. In alcoholism: (Mani, et al., 2013) In the retina: (Navneet, et al., 2019)

Note that promoting Nrf2 would not be as helpful for reducing oxidative stress, if the person was deficient in the ability to make cysteine from homocysteine (CBS gene dysfunction for example, a main cause of elevated homocysteine); or had an inability to make Dimethylglycine from betaine (BHMT gene dysfunction); or lacked some methyl B vitamins or choline. That would include me, before I started supplementing with DMG and other methyl B vitamins.

• Any level of physical activity helped reduce homocysteine levels in an elderly population. (Dankner, Chetrit, Lubin, Sela, 2004)

“Folate-Mediated One-Carbon Metabolism (FOCM)” (One Carbon Methylation Cycle) (Hayden, Tyagi, 2022, Figure 1)

C) Hyper-homocysteinemia or homocystinuria.

Long-term risks of elevated homocysteine include cardiovascular conditions like atherosclerosis and Congestive Heart Failure, and may also include age-related macular degeneration, hearing loss, and Alzheimer's disease. (Kim, Ji., Kim, Roh, Kwon, 2018)

Elevated plasma homocysteine may be less severe while presence in the urine of elevated homocysteine, may indicate more severity. The conditions are similar. In normal function homocysteine would be converted to the amino acid methionine in two ways. Either with BHMT and the transfer of a methyl group from betaine and production of Dimethylglycine. Or with MTR and B12 as a cofactor, and the transfer of a methyl group from 5MTH (bioactive folate). (Weber Hoss, Poloni, Blom, Doederlein Schwartz, 2019; Fig. 1) Methionine is a methyl donor, (Obeid, 2103, Fig. 1), and lack of methyl donors would increase risk of unwanted epigenetic changes. Methionine, methyl folate and methyl cobalamin may interact for normal DNA methylation. (Graham, et al., 2010) Confounding variable: Microbiome dysfunction can also affect epigenetics.

The most frequent cause of elevated homocysteine is dysfunctional gene alleles in the interconnected pathways of Methionine, Methylation, Remethylation, and Transsulfuration. These pathways affect glutathione production and DNA methylation which is the epigenetic control of which genes can be transcribed.

Tangent: Some epigenetic changes can be reversed and occurs daily/nightly for many genes when our circadian cycle is functioning. If an epigenetic change remains too long it may also become more permanent, and some epigenetic changes can be transmitted to a baby. Undernutrition prenatally can cause changes in the fetal epigenetics that cause the child/adult later in their lives to be more at risk for obesity if food or calories are plentiful. In our modern lives we have an epidemic of undernutrition with an excess of calories, leading to fetal development of a malnourished child that evolution thinks is facing a time of famine. Having a metabolism set to conserve energy would be protective in a famine, but during a time of excess calories/low nutrients, it leads to greater risk for obesity. (need to add citations)

Hyperhomocysteinemia is a risk for alleles of BHMT, (BHMT, genecards), MTHFR, (MedlinePlus/MTHFR), MTRR, (MedlinePlus/MTRR), and Classical homocystinuria for high-risk alleles of CBS, one example: (rs28934891, dbSNP). (MedlinePlus/CBS) Alleles of MTR may increase conversion of homocysteine to methionine leading to low B12 – but the BHMT gene would need to be working for that to happen.

Elevated homocysteine is associated with heart disease and epigenetic problems, yet treatment focused on decreasing homocysteine does not help consistently. (Li, S., et al., 2021) The standard treatment for homocysteinemia is B6, B12, and folic acid, (Engman, 1998), rather than methyl folate/5THF and cyanocobalamin is likely the form of B12 used.

Methionine is also a methyl donor.  In Classical homocysteinuria with a CBS gene dysfunctional allele, methionine may also be elevated along with homocysteine and cysteine is low; glutathione also may be low as another downstream product of the transsulfuration (CBS enzyme) pathway. (Sbodio, Snyder, Paul, 2019) Low methionine is not necessarily a biomarker for homocystinuria. Methionine may be normal or low when MTHFR or cblC are the genes with dysfunctional alleles. (Weber Hoss, Poloni, Blom, Doederlein Schwartz, 2019; Table 2).

Excessive intake of methionine can also be a cause as homocysteine can be produced from methionine and then is either remethylated back into methionine in the one carbon cycle or homocysteine enters the transsulfuration pathway (CBS enzyme) which leads to cysteine, glutathione (GSH) or hydrogen sulfide (H2S). (Sbodio, Snyder, Paul, 2019) A high protein diet, especially with red meat and dairy foods, is going to have more homocysteine content than average. (Homocysteine reduction/LifeExtension)

Certain medications or diseases may also cause excess accumulation of homocysteine. (Kim, Ji., Kim, Roh, Kwon, 2018) *More about one of the causal diseases is included later, spoiler alert, it is malaria. I’m pausing here to take some Artemesia extract ;-).

Potential risks of elevated homocysteine.

Hyperhomocysteinemia is a cardiovascular risk, increasing risk of stroke or atherosclerosis. It also is associated with mental illness, seizures, and skeletal effects: osteoporosis and osteopenia, the NTD scoliosis, sternal deformities, tall stature, dolichostenomelia – abnormally long limbs, arachnodactyly - very long, slender fingers and/or toes, and genu valgum – knock knees, the lower limbs turn inward while the ankles remain apart, seen in younger children. (Mudd, et al., 1985; Weber, et al., 2016, cited by Weber Hoss, Poloni, Blom, Doederlein Schwartz, 2019) Lower bone density may be present in children and adults with chronically elevated homocysteine. (Weber, et al., 2016)

Hyperhomocysteinemia can cause endoplasmic reticulum stress and lead to apoptosis of cells. Expression of Endoplasmic reticulum oxidoreductase 1α (ERO1α) was down-regulated by cooperative actions of DNA methyltransferase 1 (DNMT1) and Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also called G9a, in a study with CBS +/- and CBS +/+ mice on a diet with excess methionine for 12 weeks. Liver injury was more severe in the CBS +/- mice. (Shen, et al., 2022)

Systemic inflammation, mitochondrial and oxidative stress risks occur with elevated homocysteine:

“Homocysteine (Hcy) metabolism is crucial for regulating methionine availability, protein homeostasis, and DNA-methylation presenting, therefore, key pathways in post-genomic and epigenetic regulation mechanisms. Consequently, impaired Hcy metabolism leading to elevated concentrations of Hcy in the blood plasma (hyperhomocysteinemia) is linked to the overproduction of free radicals, induced oxidative stress, mitochondrial impairments, systemic inflammation and increased risks of eye disorders, coronary artery diseases, atherosclerosis, myocardial infarction, ischemic stroke, thrombotic events, cancer development and progression, osteoporosis, neurodegenerative disorders, pregnancy complications, delayed healing processes, and poor COVID-19 outcomes, among others.”

(CC-BY the authors: Koklesova, et al., 2021)

Hyperhomocysteinemia can cause protein translational modification (PTM) with a metabolite of homocysteine. The PTM is called N-Homocysteinylation. (Sharma, Kumar, Singh, 2014) PTM of proteins is associated with increased pain sensitivity, myelin degeneration, and autoimmune antibodies being created against the protein. (various references)

DNA methylation is connected to homocysteine metabolism due to the SAM and SAH that is produced. In hyper-homocysteinemia methylation capacity drops as SAH accumulates and causes a decreased SAM/SAH ratio. More than 18 weeks of a methyl-deficient diet can cause irreversible hypomethylations of DNA. (Koklesova, et al., 2021)

“The transmethylation pathway is closely associated with epigenetic processes, including DNA methylation and histone modifications (acetylation, methylation, and N-homocysteinylation). However, these epigenetic changes also depend on several factors such as gender, diet, and/or gene mutations [28]. DNA methylation is connected to Hcy metabolism through the generation of SAM and SAH. In HHcy, the accumulation of SAH causes the decline of methylation capacity characterized by decreased SAM/SAH ratio [29]. A lack of essential one-carbon nutrients, including Met, folic acid, or choline, significantly reduces SAM and SAM/SAH ratio associated with decreased global DNA methylation. Despite the reversible changes of DNA methylation, a long-term administration (> 18 weeks) of a methyl-deficient diet causes irreversible DNA hypomethylations [30]. Further, excessive Hcy can be converted to a Hcy thiolactone that can react with the ε-amino group of a protein lysine residue (N-homocysteinylation) and contribute to the manifestations of HHcy [31]. Further, N-Homocysteinylation of both non-histone and histone residues (by increased Hcy thiolactone) represents a post-translational modification [32] that causes also alterations in gene expression [33].”

(CC-BY the authors Koklesova, et al., 2021)

Gene polymorphisms in the One Carbon Cycle pathways is the most common cause of hyperhomocysteinemia/homocystinuria.

The interconnected methionine, methylation, remethylation, and transsulfuration cycles involve eight genes, and are shown in Figure 1 by Weber Hoss, Poloni, Blom, Doederlein Schwartz, 2019, and by Obeid, 2103, in another Fig. 1. The author {me, Jennifer} has polymorphisms in five of them, and a sixth that is needed for reactivation of MTR:

• BHMT, (double, may affect function),

• SHMT, (single, Missense Variant),

• MTR, (single, Missense Variant),

• addition, not included in Fig.1, MTRR, (double, Missense Variant), is needed to reactivate MTR, so the double Missense MTRR wipes out the effectiveness of the single normal MTR gene,

• CBS, (single, not the high risk for Classical homocystinuria allele),

• and MTHFR, (double, Missense Variant).

That does not look good (for the author {me}), but it could be worse with a CBS risk allele. The MTHFR C677T dysfunction is worse at higher temperatures. It causes reduced activity of the enzyme: 50-60% lower activity at temperatures above 37’C/98.6’F, and 65% lower at temperatures above 46’C. (Rozen, 1997, cited by Raghubeer, Matsha, 2021)

Two alleles of the author, MTR/A2756G in combination with MTRR/A66G, may increase risk of elevated homocysteine more than either would as a single difference. (Laraqui, et al., 2006)

An association was found in one large epidemiologic cohort study (Nurses’ Health Study (NHS)) suggesting increased cardiovascular risk for the MTHFR rs1801133 CT variant, particularly in combination with the SHMT1 rs1979277 TT genotype. However, no correlation to cardiovascular risk or combined association was found between the two variants in the Health Professionals Follow-Up Study. (Wernimont, et al., 2011)

Retinoid Toxicity may be involved.

Clues rather than clinical trials – in cancer cells all-trans Retinoic acid (ATRA) has been found to promote homocysteine and reduce glutathione, leading to harm to cancer cells but not to normal liver cells.

The activated retinoid (ATRA) can cause elevated homocysteine - in N-acetylglucosaminyltransferase V (GnT-V) repressed human hepatocarcinoma 7721 cells (GnT-V-AS/7721 cells). Glutathione was reduced in the process, and it led to increased endoplasmic reticulum stress and apoptosis of the cancer cells. The ATRA did not modify homocysteine metabolism in normal liver cells. The ATRA repressed BHMT and CBS expression. (Xu, et al., 2010)

ATRA has been used as a cancer treatment (Nowak, Stewart, Koeffler, 2009) as Xu, et al., 2010, had considered possible, and the retinoid treatment led to side effects in some patients that resemble the hyperinflammation of COVID19 – including ground glass opacities lung scans. (Weerakkody, et al, 2012)  

Unknowns: Why is the ATRA targeting cancer cells but not normal liver cells? What other cell types might also trigger that response from ATRA? If retinoids can cause elevated homocysteine, treatment with B vitamins would be inadequate without also avoiding vitamin A, retinoid medications, and carotenoids. Since ATRA can promote homocysteine in hepatocarcinoma cells, then it likely is a pathway that can happen in other types of cells. Cancer cells are iron rich and so are infected cells in malaria. Malaria, it turns out, is a condition that can cause hyperhomocysteinemia.

The malaria parasite Plasmodium falciparum does not have a CBS gene and has a truncated transsulfuration pathway leading to elevated homocysteine, which it uses to promote gametocytogenesis, (Beri, et al., 2017), a switch to the gametocyte form that travels in the infected human’s blood to be taken up by a mosquito. Jusoh, Skinner-Adams, and Davis, 2003 tested a variety of retinoids and retinol for antimalarial treatment and found the retinol effective while ATRA and other retinoids had less impact. Retinoic acid receptor antagonists had paradoxical effects suggesting to the team that the parasite has or acquires a Retinoic acid receptor like function. (Jusoh, Skinner-Adams, and Davis, 2003)

In promyelocytic leukemia cells, miR-192-5p has shown a role in differentiation of cancer cells via regulation of Adenylate cyclase 7 (AC7) which promotes all-trans retinoic acid (ATRA)-induced differentiation of the leukemia cells into mature granulocytes. (He, B., et al., 2018) ATRA use in leukemia has become a standard of care. Remission of the over-accumulation of immature cells may occur by promoting the differentiation therapy but relapse may also occur. (Nowak, Stewart, Koeffler, 2009)

Interestingly, ATRA treatment for promyelocytic leukemia can cause negative symptoms including “ground glass opacities” on chest radiographic scans. The negative symptoms have been called “differentiation syndrome” and “all-trans retinoic acid (ATRA) syndrome.” “Other symptoms of the syndrome include fever, weight gain, respiratory distress, pleural and pericardial effusion, and pulmonary infiltrates on chest radiography.” (Weerakkody, et al, 2012)

*That symptom list seems very similar to the hyperinflammation of ‘COVID19’.

**Note that forcing cells to differentiate may reduce a problem of immature cells but it does not answer why abnormal growth is occurring.

Changes in microRNA expression are seen in many chronic conditions.

MicroRNA miR-192-5p may be involved in elevated homocysteine {theory of the author at this stage}. The microRNA miR-192-5p is reduced in bowel conditions, asthma and in the kidneys of patients with hypertension, and possibly in CBS related homocystinuria; but is elevated in some types of cancer and NAFLD.

MicroRNA are regulatory of mRNA transcription or degradation, and miR-192-5p levels may have a role in Classical homocystinuria (CBS dysfunction as the primary cause) in which reduced leptin and low-density lipoprotein levels and decreased liver enzyme stearoyl-CoA desaturase 1 (SCD-1) activity was found by Poloni, et al., 2017. A high fat diet promotes liver SCD-1 activity and miR-192-5p is increased. The microRNA appears to up-regulate SCD-1 activity. (Liu, X.L., et al., 2017) A diet high in sugar also up-regulates SCD-1 activity. MiR-192-5p protects against the lipotoxic effects of saturated fatty acids (16:0 and 18:0, nutrient or DNL derived) by converting them to monounsaturated fatty acids (16:1n-7 and 18:1n-9). (Silbernagel, et al., 2012) Unknown: Is SCD-1 low in Classical homocysteinuria due to reduced miR-192-5p?

MiR-192-5p is lower than normal in colitis/Crohn’s and is typically elevated in cancer and NAFLD. (Ren, Yao, Cai, Fang, 2021) In hepatocellular carcinoma, miR-192-5p levels were low, glycolysis was increased, and lactate levels were increased. (Gu, et al., 2020) MiR-192-5p is lower than normal in asthma and inflammation was improved with increased miR-192-5p in an animal-based study (asthma mice). There was a decrease in levels of cytokines interleukin (IL)-4, IL-5, and IL-13 and the levels of ovalbumin (OVA)-specific IgE, iNOS and COX-2, with the miR-192-5p treatment. (Lou, et al., 2020)

In NAFLD or alcoholic liver disease, microRNA differences have been observed and suggested as biomarkers for disease presence or prognosis. MiR192-5p is one of the elevated miRNAs. MicroRNAs are sent in exosomes between different types of liver cells and may advance disease process or correct it.

Choline or methionine deficient diets increase risk of excess miR-192 and miR-122, polyphenols reduced risk of fatty liver disease and miR-122.

A choline deficient diet induced more expression of miR-192 and miR-122 in an animal-based study of NAFLD. A high fat diet or choline and methionine deficient diet could also induce changes in microRNA expression in the liver, animal-based studies. (Hwang, Yang, 2021) Investigation into steatosis progressing to nonalcoholic steatohepatitis (NASH) with the choline and methionine deficient diet found an increase in serum exosomal miR-122 levels and a decrease hepatic miR-122 levels and an increase in NASH-related fibrosis. (Csak, et al., 2015, cited by Hwang, Yang, 2021) Polyphenols derived from plants were found to prevent diet-induced fatty liver disease in a hyperlipidemic mouse study by regulation of the expression of miR-122 and mirR-103-107. (Joven, et al., 2012)

Alcoholic organ damage also includes microRNA changes and exosomes delivering microRNA to other areas of the body. Retinoids and ATRA are involved as the ethanol increased activation of retinol in the liver. (Natarajan, Pachunka, Mott, 2015)

Folic acid is protective against Fetal Alcohol exposure.

Folic acid protected against fetal alcohol risks and increase in miR-10a that is seen with fetal alcohol exposure. The microRNA may be associated with ethanol increasing levels of all-trans retinoic acid. (Natarajan, Pachunka, Mott, 2015)

“Supplementation of folic acid prevented the increase in miR-10a caused due to ethanol in the fetal brain [139]. Folic acid treatment also protects cardiac birth defects in mice due to fetal alcohol syndrome [143]. Ethanol ingestion was found to dramatically increase retinol and retinoic acid receptor levels in the fetal embryo [144]. Retinoic acid receptor antagonist has been shown to inhibit the expression of miR-10a in pancreatic cancer cells [140]. Further, ethanol intoxication increases the levels of all-trans retinoic acid levels in the embryo [122,144]. Ethanol-induced increase in the levels of all-trans retinoic acid in the brain and hippocampus were due to an increase in the expression of retinoic acid synthesizing enzymes [122]. It is tempting to speculate that increased retinoic acid could be responsible for the observed increase in the expression of miR-10a and miR-10b during fetal alcohol syndrome. Further studies are needed to confirm this hypothesis of ethanol-induced retinoic acid activating retinoic acid receptor (RAR) to enhance miR-10 expression in fetal alcohol syndrome.” (CC-BY the authors: Natarajan, Pachunka, Mott, 2015, and licensee MDPI, Basel, Switzerland.)

Prenatal alcohol exposure may change microRNA levels in the brain in the next generation as well as the infant (mouse study). Cannabinoid Type 1 receptors may be reduced as a result of increases in miR-26b. Natarajan, Pachunka, Mott, 2015

“Prenatal exposure of alcohol results in life-long problems, e.g., a recent study in mice exposed to ethanol before birth showed increased miR-26b in the brain of the next generation of mice. Increased miR-26b targets and decreases the levels of cannabinoid receptor 1 (CB1R) [149]. CB1R is a G-protein coupled receptor and was shown to be abundantly present in the mammalian brain. CB1R confers neuroprotection against excitotoxicity by inducing brain-derived neurotropic factor (BDNF) via PI3K-protein kinase B(Akt)- mammalian target of Rapamycin complex 1 axis [150]. Human alcoholics also have shown a decrease in CB1R in their brain as evidenced by positron emission tomography analysis. This decreased brain CB1R was not reversible even a month after self-withdraw of alcohol consumption [151]. Further studies are needed to confirm whether miR-26 plays a role in decreasing CB1R levels in the brain of patients with alcoholism or acute alcohol exposure.” (CC-BY the authors: Natarajan, Pachunka, Mott, 2015, and licensee MDPI, Basel, Switzerland.)

*Increased expression and signaling of CB1R in the dorsolateral prefrontal cortex of alcoholics has been associated with alcoholics who committed suicide compared to chronic alcoholics. (Yaragudri, et al., 2005) {*find the prior post that discussed this topic.}

Paternal alcohol use, stress, or high fat diet can alter microRNA levels in sperm. (Natarajan, Pachunka, Mott, 2015)

“Paternal ethanol consumption was shown to decrease cytosine methyltransferase transcript levels in sperm [156]. Also, mammalian sperm-derived miR-34c has been shown to be critical for the zygote’s first cell division by targeting BCL-2 protein expression [157]. Here BCL-2 was suggested to have an anti-proliferative function by negatively regulating cyclin-dependent kinase inhibitor, p27 [157,158]. Paternal alcohol consumption and microRNA changes in the sperm have not been studied yet. However, exposure of male mice to stress or paternal stress increases several sperm microRNAs such as, miR-29c, miR-30a, miR-30c, miR-32, miR-193, miR-204, miR-375, miR-532-3p and miR-698 [159]. Similarly, high fat diet-induced obese male mice also showed global hypomethylation of sperm DNA and exhibited altered microRNAs levels [160,161]. Alcohol-induced changes in paternal microRNAs should be investigated.” (CC-BY the authors: Natarajan, Pachunka, Mott, 2015, and licensee MDPI, Basel, Switzerland.)

Medical history regarding homocysteine and cardiovascular health:

The author takes methyl B complex supplements and other B vitamins and has had no medical history of elevated homocysteine, however vasculitis symptoms are present and the author plans to visit a cardiologist for a diagnostic screening. The author had noted being sensitive to heat and having reduced endurance in hot temperatures. Methyl folate and cyanocobalamin, riboflavin, B6, zinc, choline, Dimethylglycine (DMG) and methionine are supplements used by the author on most days. Inconsistency is a problem in treatment for the author. Migraines are a symptom when DMG is missed too many days in a row. Scalded tongue B vitamin deficiency symptoms or increased finger tingling and numbness are symptoms when the methyl B and other B vitamins are missed too often. Epsom salt is used about once a week in baths for a topical magnesium and sulfate source and symptoms of muscle cramps and increased anxiety may occur if that is delayed too long. More often than every three days is too much magnesium for the author’s current needs. Dose makes the medicine.

Physically, the author resembled the knock knee-ed gangly child described by Mudd, et al., 1985; and Weber, et al., 2016, as cited by Weber Hoss, Poloni, Blom, Doederlein Schwartz, 2019. Low bone density has been found in early screenings for osteoporosis. What sternal irregularities might mean, is unknown to the author, however a slight skewed torticullis effect is present in her skeletal formation and the left side of the body is (very) slightly smaller or different than the right side. Early symptoms of osteoarthritis are present.

~

This post is already too long for the email and doesn’t even include the references except for a few additions. In finding out only two of the “certain diseases” (Kim, Ji., Kim, Roh, Kwon, 2018) that can cause hyperhomocysteinemia (malaria and alcoholism), my next step is to look for more of those other causal conditions - there be clues in them thar depths. My work is limited by budget as I typically do not pay for articles unless they seem critically super useful. I may buy the $65 dollar one as it looks super useful. (The reference mentioning “other conditions” was behind a paywall. Abstracts can be very informative though and I appreciate having open access to as many papers as are available. There will likely be a follow-up.

And this doesn’t even include the IL-6/zinc deficiency section - different topic. Health is so much fun - when you have it. I was a congested child who could rarely breathe through both nostrils - having one clear was a good day. I also had chronic eczema and was the only sibling to get chicken pox severely. Not identifying gene polymorphisms that affect metabolism in our children (or adults) is stupid or by design of the medical industry.

It is hard to know which is true as the medical industry still recommends folic acid and cyanocobalamin instead of the bioactive forms.

Disclaimer: This 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

(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).

(Mani, et al., 2013) Mani, M., Khaghani, S., Gol Mohammadi, T., Zamani, Z., Azadmanesh, K., et al. (2013). Activation of Nrf2-Antioxidant Response Element Mediated Glutamate Cysteine Ligase Expression in Hepatoma Cell line by Homocysteine. Hepat Mon. 13(5):e8394. doi: 10.5812/hepatmon.8394. Available at: https://brieflands.com/articles/hepatmon-15240.html (Accessed: 4 Dec 2022)

(Navneet, et al., 2019) Navneet, S., Cui, X., Zhao, J., Wang, J., Kaidery, N.A., Thomas, B., Bollinger, K.E., Yoon, Y., Smith, S.B., (2019). Excess homocysteine upregulates the NRF2-antioxidant pathway in retinal Müller glial cells. Exp Eye Res. Jan;178:228-237. doi: 10.1016/j.exer.2018.03.022. Epub 2018 Mar 31. PMID: 29608906; PMCID: PMC6167214. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167214/ (Accessed 4 Dec 2022)

(Yaragudri, et al., 2005) Yaragudri, V., Arango, V., Xie, S., Kassir, S., Mann, J., Cooper, T., Hungund, B., (2005). Elevated levels of endocannabinoids and CB1 receptor-mediated G-protein signaling in the prefrontal cortex of alcoholic suicide victims. Biological psychiatry. 57:480-6. 10.1016/j.biopsych.2004.11.033. Available at: https://www.researchgate.net/publication/7995593_Elevated_levels_of_endocannabinoids_and_CB1_receptor-mediated_G-protein_signaling_in_the_prefrontal_cortex_of_alcoholic_suicide_victims (Accessed: 4 Dec 2022)