Anti-malarial herbs, Cox-2 inhibition leading to folate and methylation cycle inhibition - that's not good for healthy cells, but useful against cancer cells.

This is another reminder that some can be good, but too much of many things can become a negative. Plant phytonutrients often are intended to ward off predator insects or fight microbial pathogens.

My question was (on July 12th): Might my drinking too much Wormwood tea for a while now, have added to my sudden hair loss? and the short answer is yes.

*Brave AI failed the adequate citation test but provided interesting info on malaria and potential mechanism of action of Wormwood, whole herb/extract. I am posting this with the intention to dig deeper into how Wormwood has modulator effects. It can up or down regulate folate methylation as needed - helping protect against heavy metal toxicity, or killing cancer or malaria infected cells by inhibition of a folate enzyme. That is smart medicine, nature medicine which suggests microRNA to me. Synergistic effects have been found from use of the whole herb, Artemesia absintheium - the whole is more potent than single phytonutrient extracts.

Also see Prenatal/Child page on jenniferdepew.com for more about Artemesia species and cautions. Dandelion leaf and root would be safe for women of child bearing age and children. Have enough zinc too, for zinc ionophore potency against microbes or malaria or cancer.

https://jenniferdepew.com/prenatal%2Fchild

Wormwood tea adds to salicylate excess for me and salicylates and other polyphenols in wormwood or my pomegranate peel could be inhibiting an enzyme which is critically needed for the folate methylation cycle. Inhibition of folate methylation cycle, then can also inhibit the interconnected cycles which include the sulfate and biopterin/BH4 cycles.

Artemesia is a plant group with many species, all fairly pormtent, and Mugwort is a similar plant group. Between the two, a medicinal plant is likely growing in your local region. Photo by Mathias Katz on Unsplash

Folate metabolism also »> purine nucleotides and »> DNA and RNA

Inhibition of folate metabolism also reduces nucleotide production and hair follicles are rapidly growing cells that need a lot of folate and nucleotides - so lack of methylation cycle function can lead to Telogen effluvium and early or sudden hair loss.

“The mechanism of action of Artemisia absinthe against malaria is thought to involve the inhibition of the DHFR enzyme, which is essential for the survival of the malaria parasite.”

Two enzymes are critical, the first SLC19A1 helps move dietary sourced folate from the exterior of the cell, or antifolates or folic acid, into the interior of the cell to be used in the methylation cycles. The SLC19A1 enzyme helps it cross the intestinal lining and enter the cell as DHF; and then, the second critically important enzyme, DHFR, helps transform the folate or folate-like substance into THF which is part of the methylation cycles.

Chemicals that can inhibit the DHFR enzyme include excess folic acid

(and likely that means an excess of a folate supplement too - but my reference used the word ‘folic acid’).

The enzyme DHFR may be inhibited by excess folic acid, or by nicotine, or methotrexate. Salicylates, aspirin and NSAIDS can also inhibit the enzyme and Polyphenols like EGCG and grapefruit seed extract also may inhibit the enzyme. And this likely also includes my Wormwood tea or Sweet Wormwood tea. Artemisinin as an extract I am less sure about.

This means that an excess of ‘healthy’ phytonutrients could be back-firing if methylation function is being inhibited for normal cells instead of just for cancer or infected cells.

Too little of required Cofactors for the DHFR enzyme could also limit its function

- niacin & nucleotides might be dietary support.

• The DHFR enzyme needs niacin/NADPH as a cofactor, so lack of B3 may limit methylation function.

• BH2 from the biopterin part of the interlinked methylation cycles is also needed.

What is biopterin? Do we need to eat it?

No, but eating nucleotides might help, especially if health and metabolic function is aged, fragile or weak.

Biopterin - Nutrient Metabolism - Doctor Steve Abel

December 7, 2020 - Requirements: The body can produce adequate amounts in the absence of dietary intake; synthesis requires GTP, niacin and magnesium. Food sources: While many animal foods contain various bioactive forms of biopterin the amounts have not been well investigated.

GTP is a nucleotide found in RNA, which we can make, but which we can also consume in our diet, saving us metabolic work. Good sources of dietary nucleotides include sardines, organ meats or gristly bits of meat, and nutritional yeast flakes (NYF). About two teaspoons of NYF per day might be helpful for vegans - it is not the same as Baker’s yeast or live Brewer’s yeast. Nutritional yeast flakes are heat treated and are no longer a live yeast, which we don’t want growing in excess in our gut.

The biochemistry of the DHFR enzyme and graphic below

The folate methylation cycle within the cell’s interior is shown in the image below. It shows a cell membrane as an arcing dotted line near the top. Above that the intestinal walls are represented by wavy dotted lines. Within that intestinal tube, would be flowing a mix of food, supplements, and/or any antifolate medications that were consumed/swallowed.

An enzyme, SLC19A1, is needed to help the folate substrate from the blood enter into a cell. That converts it into DHF, dihydrofolate (?) which then needs the enzyme DHFR to continue in the folate cycle to become tetrahydrofolate, (THF), or 5MTF, the more active forms. DHFR needs the flush niacin/B3 derivative, NADPH as a cofactor. The enzyme can be inhibited by nicotine, folic acid, methotrexate, EGCG, NSAIDS, aspirin, and grapefruit seed extract. It also uses a BH2 from the biopterin recycling pathway. BH2 is converted to BH4, potassium (K+) and ATP.

In the image below, DHFR is in the center, underlined with an orange and purple bar.

To highlight »> The DHFR enzyme can be inhibited by nicotine, folic acid, methotrexate, EGCG, NSAIDS, aspirin, and grapefruit seed extract.

That list made me wonder if Wormwood would also inhibit that enzyme - and inhibit the methylation cycle. That can be desirable to kill cancer cells, or a malaria parasite - but wouldn’t be desirable for my hair follicles, perhaps - Brave AI search results follow. I have really been enjoying Wormwood tea, for a while now, and had wondered if it added to my salicylate excess - Yes, it does. I cut out vanilla to help make it work at all. And if that maybe had added to my hair loss. And the answer is maybe yes.

My general lack of consistent use of my supplements and DMG containing Cheerful Juice would also have negatively affected my methylation cycle function. Hair follicles are a rapidly growing cell type which means they need a lot of folate.

Folate in Telogen effluvium

So, yes is the answer. Folate helps support hair follicle cell growth and that helps to prevent Telogen effluvium (TE). Telogen effluvium is referring to a stage of hair growth -- the end stage. Normally only a few hairs at a time would be falling out and starting over. In telogen effluvium, lots of hair follicles all decide that they are done growing that hair, which then will fall out and hopefully a new hair starts growing rather than baldness.

Folate deficiency has been linked to the development of TE, and supplementation may help. In particular, vitamin D, ferritin, and zinc deficiencies have been found to be prevalent in people with Telogen effluvium. (Cheung, et al., 2016) (Brave AI search summary)

“Many prior studies have either supported or failed to find a correlation between telogen effluvium and deficiencies in vitamins and minerals, in particular, vitamin D, ferritin, vitamin B12, folate, and zinc. We performed a retrospective cross-sectional study of patients with telogen effluvium in the greater Pittsburgh, Pennsylvania area, and measured the rates of these deficiencies. Our results demonstrate that the prevalence of vitamin D, ferritin, and zinc deficiencies is non-trivial and therefore justifies including these laboratory studies in initial clinical evaluation.” (Cheung, et al., 2016)

DHFR enzyme and Wormwood - Artemisia absinthe - Brave AI summary

*Sweet Wormwood would be the herb recommended to buy for preventive self-care, as it doesn’t have thujone (seizure risk in excess - affects GABA) and is less bitter in flavor, but I bought the wrong kind and have grown to really like it.

“Thujone: A ketone monoterpene, this compound blocks GABA receptors, which are neurotransmitters, making thujone a neurotoxin. The side effects include vomiting and seizures. Thujone content in Wormwood is increased through distillation. (Hold 2000).” (evergreen.edu)

“Thujone, a terpene found in oil of wormwood with α and β isomers, is the suspected source of hallucinations and psychosis from absinthe use [86]. Thujone has been shown to antagonize the γ-aminobutyric acid (GABA) receptor, and this may explain absinthe's excitatory and seizure-producing effects.

Acute effects of absinthe ingestion produce euphoria, confusion, delirium, and hallucinations, and it has also been described as an aphrodisiac [82–84]. Chronic use of absinthe, a syndrome referred to as absinthism, is reported to cause gastrointestinal disorders, sleeplessness, tremors, convulsions, auditory and visual hallucinations, brain damage, and death [82,85,87]. Because of acute and chronic effects, absinthe was banned in some countries in the early twentieth century, including the United States in 1912 [81,85]. There continues to be debate over the cause of absinthism: high alcohol content leading to alcoholism, natural components in wormwood oil, or adulteration [88].”

Medical Toxicology, William H. RichardsonIII MD, ... Jill E. Michels PharmD, in Emergency Medicine Clinics of North America, 2007, viewable at Artemisia Absinthium - an overview | ScienceDirect Topics *last article

There are many non-thujone containing species of Artemesia and Mugworts, and they are all fairly potent medicinals, in similar ways, from what I’ve read in the past.

“Besides its significance in flavouring, wormwood has a long history of therapeutic use both in folk medicine and in modern pharmacology. The essential oil of this plant has been used in anthelmintic, anti cold, anti-inflammatory and antimicrobial preparations and for its antiseptic, antidepressant, digestive, carminative, stimulant, choleretic and tonic effects (Goud and Swamy, 2015; Watson and Preedy, 2008)” Sources of variability of wormwood (Artemisia absinthium L.) essential oil, Huong Thi Nguyen, Zámboriné Éva Németh, in Journal of Applied Research on Medicinal and Aromatic Plants, 2016, Section: 2 Characteristics and significance of Artemisia absinthium L. viewable at Artemisia Absinthium - an overview | ScienceDirect Topics *first article

“In a study at Yale University, patients from five locations in Germany with Crohn’s disease were administered an herbal blend containing wormwood herb (3 × 500 mg/day), or placebo, for a ten week period. It was observed that patients consuming the herb blend were able to get free of steroids − the conventional treatment of this disease − and the treatment improved their mood and quality of life (Omer et al., 2007). Similar findings were published by Krebs et al. (2010) administering 3 × 750 mg dried powdered wormwood for 6 weeks in addition to their basic Crohn’s disease therapy. In animal experiments, Bora and Sharma (2010) detected neuroprotective effects of wormwood on focal ischemia and reperfusion-induced cerebral injury and this finding was ascertained by Lachenmeier (2010), too.” Sources of variability of wormwood (Artemisia absinthium L.) essential oil, Section: 4 Physiological and therapeutic effects. Viewable at Artemisia Absinthium - an overview | ScienceDirect Topics *second to last article

Dose makes the medicine or the poison. Making a hot tea brought out significantly more of the thujone containing plant oils and my first cup was a bit zippy. Now I make it by the Sun Tea method - a glass liter bottle with cold water and a teaspoon of dried Wormwood leaf (I bought a pound, it may last me until pole-shift). Leave in the sun, or even just leave it out overnight. It seems to turn into a structured water tea even without the sunshine/infrared heat. Polyphenols help support the organization or quantum structuring of Exclusion Zones within water. (previous post series - ‘Gerald Pollack’ in my archives or ‘structured water’)

One liter a day, one teaspoon, would be equivalent to a anti-malarial preventive routine in areas of Africa with malaria mosquitos. I have found trying to keep it at that or less seems okay compared to a couple liters a day. A ‘No Fenol’ enzyme product by Houston Enzymes helps a little but not much. Having less helps more.

**Brave AI saves me time when only a brief look is needed - but I have found some errors, so it not 100% reliable - Bing is worse though.

Brave AI summary introduction - the references (first search) didn’t support this information so I did a new search with the same phrase and got more detail. - This is now somewhat rewritten by me.

Wormwood and other Artemesia species are a family of plants which have been used in traditional medicine for various purposes, including the treatment of malaria. Wormwood (Artemisia absinthium) has been studied for its potential therapeutic effects, including its ability to modulate enzymes involved in redox balance and detoxification. The Dihydrofolate Reductase (DHFR) enzyme, is an essential enzyme in the folate biosynthesis pathway. In the context of malaria, the DHFR enzyme is a target for antimalarial drugs.

In vitro and in vivo studies show that Wormwood has a modulatory role — it may up or down regulate the DHFR enzyme, possibly depending on current need.

• Research has shown that Artemisia absinthium extract can inhibit DHFR activity in vitro, potentially contributing to its antioxidant and anti-inflammatory effects (Szopa et al., 2020).

• In vivo studies have demonstrated that wormwood extract can restore DHFR activity perturbed by lead exposure, indicating a protective role against oxidative damage (Beshay et al., 2018).

Mechanistic insights:

• The bioactive compounds present in wormwood, such as flavonoids and phenolic acids, may contribute to its ability to modulate DHFR activity and redox balance (El-Saber Batitha et al., 2020).

• The antioxidant properties of wormwood may help mitigate oxidative stress-induced DHFR inhibition, thereby maintaining folate metabolism and redox homeostasis.

Clinical relevance:

• Further research is needed to fully understand the clinical implications of wormwood’s DHFR-modulating effects. However, potential applications may include the use of wormwood as a natural adjunct therapy for conditions characterized by oxidative stress and folate metabolism imbalance.

In summary, the available evidence suggests that wormwood (Artemisia absinthium) may modulate DHFR enzyme activity, potentially contributing to its antioxidant and anti-inflammatory effects. Further studies are necessary to elucidate the mechanisms and clinical relevance of this interaction.

Antimalarial Activity of Artemisia Absinthium

Studies have shown that Artemisia absinthium has antimalarial properties, which may be attributed to its ability to inhibit the DHFR enzyme. The extracts of Artemisia absinthium have been found to exhibit potent antimalarial activity against Plasmodium falciparum, the parasite responsible for malaria.

Mechanism of Action

The mechanism of action of Artemisia absinthium against malaria is thought to involve the inhibition of the DHFR enzyme, which is essential for the survival of the malaria parasite. The enzyme is responsible for reducing dihydrofolate to tetrahydrofolate, a coenzyme that is necessary for the synthesis of nucleotides. By inhibiting the DHFR enzyme, Artemisia absinthium may prevent the parasite from synthesizing the necessary nucleotides, ultimately leading to its death.

Inhibition of DHFR Enzyme

Studies have shown that Artemisia absinthium extracts contain compounds that can inhibit the activity of DHFR enzyme. For example, a study analyzing the chemical composition of Artemisia absinthium ethyl acetate and aqueous extracts found that these extracts contained phenolic compounds, flavonoids, and condensed tannins, which exhibited antioxidant and enzyme-inhibiting activities, including DHFR inhibition.

The exact mechanisms of DHFR inhibition by Artemisia absinthium extracts are not fully understood, but it is thought that the plant’s bioactive compounds may interact with the enzyme’s active site or alter its conformation, thereby reducing its activity. The presence of synergistic effects between different compounds in the extracts may also contribute to the observed inhibition.

Key Takeaways

• Artemisia absinthium extracts contain compounds that can inhibit the activity of DHFR enzyme.

• The inhibition may be due to interactions with the enzyme’s active site or alterations in its conformation.

• Synergistic effects between different compounds in the extracts may contribute to the observed inhibition.

• Further research is needed to explore the potential therapeutic applications of Artemisia absinthium extracts in the treatment of diseases where DHFR is a target enzyme.

Conclusion

In summary, Artemisia absinthium has been found to have antimalarial properties, which may be attributed to its ability to inhibit the DHFR enzyme. The enzyme is an essential target for antimalarial drugs, and the inhibition of DHFR by Artemisia absinthium may provide a new avenue for the development of antimalarial therapies.

Potential Applications

The inhibition of DHFR enzyme by Artemisia absinthium extracts may have implications for the treatment of malaria and other diseases where DHFR is a target enzyme. Further research is needed to fully elucidate the mechanisms of inhibition and to evaluate the potential therapeutic applications of Artemisia absinthium extracts

Context - I am still not seeing where the AI got the malaria mechanism of action information.

www.verywellhealth.com, Wormwood: Benefits, Risks, and Side Effects - CAUTION - Wormwood and most Artemesia species, (Artemesia afra might be safer) are not safe for children or pregnancy. Greater amounts may have been used to promote a miscarriage/abortion in past centuries.

*Note to feminists - if a woman doesn’t want to continue a pregnancy, there are varied herbals that have been used in past history. Just because modern life policies are passed doesn’t mean that modern life is the only way people can function or have functioned in the past.

www.ncbi.nlm.nih.gov, Role of Wormwood (Artemisia Absinthium) Extract on Oxidative Stress in Ameliorating Lead Induced Haematotoxicity - PMC

www.sciencedirect.com, Artemisia Absinthium - an overv

1. www.sciencedirect.com, Artemisia Absinthium - an overview | ScienceDirect Topics

2. www.ncbi.nlm.nih.gov, Artemisia absinthium L. Aqueous and Ethyl Acetate Extracts: Antioxidant Effect and Potential Activity In Vitro and In Vivo against Pancreatic α-Amylase and Intestinal α-Glucosidase - PMC - this article isn’t on topic.

3. www.sciencedirect.com, Tolerability of Artemisia absinthiu - this article isn’t on topic either but is interesting. Wormwood helped mitigate zinc deficiency in an animal based study seemingly by reducing oxidative stress and improving the anorexia/loss of appetite which can occur with zinc deficiency.

Folate & Hair follicles - Telogen Effluvium links

1. www.ncbi.nlm.nih.gov, Telogen Effluvium: A Review - PMC

2. www.healthline.com, Telogen Effluvium: Causes, Regrowth, and More

3. pubmed.ncbi.nlm.nih.gov, Telogen effluvium. New concepts and review - PubMed

4. (Cheung, et al., 2016) Cheung EJ, Sink JR, English Iii JC. Vitamin and Mineral Deficiencies in Patients With Telogen Effluvium: A Retrospective Cross-Sectional Study. J Drugs Dermatol. 2016 Oct 1;15(10):1235-1237. PMID: 27741341. https://pubmed.ncbi.nlm.nih.gov/27741341/.

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