Artemisinin, arteannuin-B, sgp130Fc and COVID-19

I’m more of a blogger, or early Christmas present giver, than may be ideal for a book author. I’ve been working on a section of my new book that might be beneficial for SARS-CoV-2 prevention and COVID-19 treatment. It may also help explain what makes some people more susceptible for developing severe COVID-19 illness rather than remaining asymptomatic as others who test positive for the SARS-CoV-2 virus.

The book is in very early stages but is 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. I’m copying the artemisinin section here in case it may be helpful. The theme of the book is not CoV specific so the excerpt is also including it within a larger topic.

The too long;didn’t read – a different extract of wormwood, arteannuin-B, may be a more effective anti-viral and anti-inflammatory, than the artemisinin; while the artemisinin may help with a chronic anemia of inflammation type iron overload problem, which may occur with COVID-19 recovery or when the illness is severe. Artemisinin has also been found useful for autoimmune disease and possibly as a cancer treatment. The bigger CoV specific information is a theory about interleuken-6 (IL-6) and a genetic difference that may explain why some people can be asymptomatic carriers of the virus – their immune system doesn’t overreact to IL-6 – and for those more at risk for over-reacting a protein our body normally makes (sgp130Fc) may be an effective treatment because it would just be needed in the overactive amount (five times the normal level).

Merry Christmas – I never could save a present I bought early.

Autoimmune Disease and other Chronic conditions

What if you are feeling so sick that nothing seems cheerful? There are no guarantees that eating healthier will be a cure-all, however you don’t know without trying and some symptom relief might be possible at least. Giving time a chance to help may also help. It can take seven days for the intestinal lining to start to heal and longer for most other areas of the body. Take care of your brain because most types of brain cells do not get replaced regularly the way that cells throughout the rest of the body are retired and replaced with new cells. The advantage in the foods and phytonutrients that tip the body away from inflammatory pathways and towards the production of antioxidants and increased immune function is modulation – moderation.

Immunomodulators and other types of modulating chemicals can shift the activity slightly towards more active or less active. An overactive immune system can also be dangerous. Modulation can be moderate – just the right amount of activity. The healing foods and phytonutrients may help moderately increase immune activity without over activating it into an autoimmune level of action. And they may moderately inhibit the inflammatory pathways without suppressing them totally as may occur with immunosuppressive drugs. During an infection we need the inflammatory pathways but we do not need an overactive response.

Too many inflammatory chemicals can lead to their attacking our healthy body cells in an immune response called a Cytokine Storm or Sepsis Shock. An autoimmune over-reaction may involve molecular mimicry where a food protein or other substance that is similar to our own body’s chemicals sets off an allergic type of immune response against the body chemical, not just the dietary protein.

Wormwood, Artemisia annua, an anti-malarial herb used in Traditional Chinese Medicine, and source of Artemisinin and arteannuin-B .

Wormwood is a medicinal herb used in Traditional Chinese Medicine (TCM). An extract of it is used to treat malaria. Artemisinin, the extract, has also been found to help modulate the immune system, which may be helpful for the treatment of autoimmune disease. Derivatives of artemisinin have also been studied for use as antiviral and anticancer treatments. (52⁸⁷) White blood cells can help identify, kill, and remove infected, damaged, or cancerous cells in a process called autophagy however the response can also become overactive in the case of autoimmune disease or a cytokine storm.

Immunomodulating herbs and drugs can help stimulate an immune response while also inhibiting too large of a response. Artemisinin was found to be helpful for rheumatoid arthritis, which has been shown to be due to a pathogen with an intracellular form, (53⁸⁸), and not helpful for osteoarthritis which is due to overuse or other physical trauma. (54⁸⁹) Artemisinin is a phytonutrient extract of the herb wormwood. It is used as a malaria treatment and in Africa ten grams of the dried herb may be used daily as a prevention against malaria, a mosquito borne parasitic disease affecting blood cells. (55⁹⁰)

The whole herb, wormwood (Artemisia annua), may contain other phytonutrients with stronger anti-viral effects than artemisinin, as whole herb extracts were found more effective against the SARS-CoV-2 virus than artemisinin alone (cell-based study). The World Health Organization (W.H.O.) expressed concern that use of a whole herb extract for non malarial illness in the population might result in an increase in artemisinin-resistant malaria strains. (56⁹¹) That concern may be overlooking the synergistic – additive – effect phytonutrients within a plant may have.

Many plants have phytonutrients that work together beneficially, helping health in different ways that have an additive effect: one may help offset a negative effect of another, or one may help one symptom and another might help a different symptom. Ginger root, for example, has over 400 bioactive phytonutrients.

Artemisinin chemically is a sesquiterpene lactone – an aromatic terpene. Two strains of Artemisia annua were chemically analyzed and found to have slightly different ratios and types of sesquiterpenes and terpenes, (57⁹²) so other aromatic chemicals in the whole herb may also be helping health in various ways. One in particular, arteannuin-B, has been found to work with artemisinin against the malaria parasite in a combination that was more effective than if the artemisinin was used alone. (58⁹³) Switching to a whole herb extract or using the combination of arteannuin-B and artemisinin might reduce the risk of the malaria parasite becoming artemisinin resistant instead of increasing the risk about which the W.H.O. expressed concern. (56⁹⁴)

Bioactive – chemicals with some biological effect within our bodies, it might be beneficial or harmful for a particular person depending on the person’s underlying level of health or genetic differences, or gender, age or other factors.

Artemisinin chemically is attracted to cells with excess iron which infectious microbes need for growth and so do cancer cells. The phytonutrient can stop protein replication within the iron rich cell which stops the replication of the infectious microbe. It also seems to bind with the excess iron which in itself can cause oxidative damage – rust might be a more familiar term for oxidative damage affecting iron. If Rheumatoid arthritis is due to an intracellular pathogen then artemisinin may be helping by stopping the underlying infection. It can help in cancer because cancer cells also tend to have extra iron and it may be helpful for the anemia of chronic inflammation which also involves excess iron in cell storage instead of being used to carry oxygen within red blood cells and may be involved in symptoms of extreme tiredness during later stages or recovery from an infection.

The amazing thing about artemisinin in comparison to other antimalarial medications is a low toxicity risk comparatively. Healthy cells are not targeted. Normal function does not seem to be disrupted although it may have pro-inflammatory effects. Arteannuin-B, on the other hand, has been found to have significant anti-inflammatory effects:

Arteannuin-B inhibits the LPS-activated production of PGE2 four times more than artemisinin or dihydroartemisin, and it has a strong inhibitory effect on the proinflammatory interleukines IL-1β, IL-6, TNF-α.”. (Lutgen 2013, 58⁹⁵)

Reducing interleukin-6 levels would likely be helpful for treating COVID-19 illness. It is increased by the SARS-CoV-2 virus and by the infection process naturally. It can help fight infection and has pro and anti-inflammatory types. A protein (sgp130Fc) helps control the pro-inflammatory type but it is normally present in amounts lower than would be needed during later stages of COVID-19 illness (the name of the disease caused by an infection with the SARS-CoV-2 coronavirus, a new virus in the group of cold and influenza viruses). Providing sgp130Fc as a treatment may help treat the people with the more severe inflammatory reaction. There seems to be a genetic susceptibility regarding the over sensitivity to IL-6 levels which may help explain why some people don’t get very sick and others get severely ill with a SARS-CoV-2 infection. (59⁹⁶)

Recent studies about polymorphism within the IL-6R genes, showed how some IL-6 Receptor variants could be a much better substrate for the shedding protease ADAM17, resulting in a reduced response to inflammation and infectious states, in terms of sIL-6R increase [68]. Those individuals are also protected from many chronic inflammatory diseases [69].” (59⁹⁷)

This theory, if true, could help point out who is more at risk for a severe immune reaction to a SARS-CoV-2 infection – people with chronic inflammatory diseases – it suggests they have the more active immune response by their IL-6 Receptor. Knowing who is more at risk can help identify who needs to be more self-protective and who may benefit from preventive treatment or early treatment for suspected symptoms. And they may be the people who might be helped by providing the protein sgp130Fc that inhibits the pro- inflammatory IL-6 Receptor. There is enough of the inhibiting protein to block the receptor activity during normal health but the level of IL-6 can increase five-fold during an infection – while no extra sgp130Fc is made. The excess IL-6 starts inflammatory activity in surrounding cells creating an increasing inflammatory response. (59⁹⁸)

Panic? Or use the information about our genetic immune responses and infection risks to be more proactive about our own health? or our communities’ health?

We can defend from within by providing our bodies with the extra nutrients that our unique genetic metabolism or infection or disease may require for our cells to cope. Vitamin C and other antioxidants and phytonutrients can also help reduce IL-6 and other inflammatory chemicals.

~~~~ end of book excerpt as it was written

addition: The protein sgp130Fc has also been found helpful to treat an animal model of Rheumatoid arthritis. The treatment used was 2.5 mg/kg which was given intravenously to the animals daily three weeks after the induction of the disease condition. Thy hypothesis that the treatment would also improve vascular health in the animals was not disproved. (60) Vascular health is commonly negatively effected in Rheumatoid arthritis along with the symptoms of swollen and painful joints, typically starting in the fingers and toes and progressing to the feet and ankles.

The protein sgp130Fc may also be helpful for treating ulcerative colitis and Irritable Bowel Syndrome. It is tested in human clinical trials for the two bowel conditions by Ferring Pharmaceuticals and I-MAB Biopharma. The version of the protein being produced and tested by the pharmaceutical companies is being called Olamkicept. (61)

The protein may also affect the risk of Alzheimer’s dementia or other inflammatory brain conditions. The protein does not cross the blood brain barrier but affects throughout the rest of the body may still affect the brain by causing an increase of soluble interleuken-6 Receptors which then can increase brain inflammation. The spg130Fc would need to be delivered into the brain somehow to inhibit the soluble IL-6 R and reduce inflammation. (61)

Maybe it would help reduce the amount of the soluble IL-6 Receptors that would be available to enter the brain if given intravenously within general circulation, I don’t know enough about this topic. It is nice to have some hope though. Previous treatment approaches for Alzheimer’s dementia have focused on reducing amyloid protein and it has not been found very helpful for improving the condition.

Pomegranate polyphenols (ellagic acid) can cross the blood brain barrier after metabolism by intestinal bacteria transforms them into urolithins. (62) Pomegranate peel extract also has been used to help form nanoparticles. Urolithin a is being given orally as a nanoparticle to help reduce oxidative stress during treatment with the cancer drug cisplatin. Mortality rate improved in an animal-based study with the addition of the urolithin a. (63) Maybe a combination of spg130Fc and urolithin could cross the blood brain barrier.

Cautions for use of spg130Fc may be needed if liver disease is present, and use for cancer treatment would be dependent on the specific cancer type. It might help treat some types and worsen other types. (61)

Disclaimer: This information is provided for educational purposes within the guidelines of Fair Use. It is not intended to provide individual guidance. Please seek a health care provider for individualized health care guidance.

Reference List

Hesperidin and Quercetin content in Citrus peel.

Based on yield ranges in a review article (1), the whole citrus peel, colorful zest and white pith layers, contained across a variety of types of citrus, greater than 2000 micrograms/gram Fresh Weight (ug/gr FW) Quercetin Equivalents (group of similar chemicals), and 83-234 milligram/gram Fresh Weight (mg/gr FW) Hesperidin (for an average of 158.5 mg/gr FW). (1)

  • An average size navel orange weighed 212.18 grams, ~ 7.5 ounces
  • and yielded 32.48 gram orange zest peel, ~ 1 ounce
  • 32.30 white pith peel, ~ 1 ounce
  • 144.49 orange wedges, ~ 5.2 ounces
  • small amount of unusable trimmings.

The citrus peel may contain 64 milligrams of quercetin and 5120 milligrams of hesperidin in the whole peel – the original measurements were of whole citrus peel (1) so it is unknown how much the white pith contains in comparison to the orange zest layer which likely contains more of the bitter tasting phytonutrients. Hesperidin was reported as being most prevalent of flavonoids being measured and equivalent across thin and thick skinned citrus species suggesting that more is in the thin zest layer (the flavedo) than the thick white pith layer (the albedo). (1, 4)

The white pith layer would likely contain a majority of the beneficial fiber and pectin, which makes up 64% of the whole peel of oranges, (1), or at least 21 grams of the yield of white pith or the orange zest in this example would be fiber/pectin. The jam in the last post had thickened even without the added pectin which led to it being too firm of a gel.

Citrus peel, the white pith, albedo layer, and the orange zest, flavedo layer, with the orange.

Health benefits may be provided from both types but in varying concentration. When I am feeling congested the pith of the whole orange is enough to clear the congestion and to help me breath more clearly again. See this post: Bitter taste receptors in the lungs & Hesperidin’s decongestant properties. Some of the zest is remaining on the white pith layer in small amounts too, but it is potent in flavor. The citrus peel jam in the last post is stronger in flavor than the white pith and a generous spoonful is plenty for a serving, and I usually mix it with other foods rather than eating it all at once.

The orange zest when minced made about a quarter cup/25 grams so the amount of 2 1/2 cups citrus zest in the jam recipe may have 250 grams potentially containing the majority of the 5120 mg of hesperidin per ounce – roughly 5000 x 10 1/4 cups = 50,000 mg for the 6 cup yield, 8,330 mg/cup or 1040 mg per two tablespoon serving of the Citrus Fig Marmalade/Jam, last post.

How much might be too much hesperidin? roughly about 28 oranges if 5120 milligrams were available with each pith layer of the peel that is eaten – however just one or two oranges per day, spaced out across the day, were good for my symptoms of congestion while I was ill, or when I am congested with spring allergies. The potentially Lethal Dose for 50% of lab animals for hesperidin, the LD50 dose, is 2000 mg/Kg. (2)

Hesperidin, rutin, citrus bioflavonoids are mildly estrogenic (so is resveratrol) and may be helpful against endometrial cancer. (2) Hesperidin may help against endometrial cancer cells by down-regulating estrogen receptors/progesterone & increasing apoptosis of the tumorous cells. (5) Bioflavonoids also seem to help reduce risk of Metabolic Syndrome, and related problems of obesity, high blood pressure, and insulin resistance, and reduce risk of cardiovascular problems. (3, 4, 6) Hesperidin can help reduce capillary fragility (6) – potentially preventing microvascular hemorrhages. More about the potential anti-viral and other health benefits of hesperidin and citrus bioflavonoids is in the post: Bitter taste receptors in the lungs & Hesperidin’s decongestant properties.

Disclaimer: This information is provided for educational purposes within the guidelines of Fair Use. It is not intended to provide individual guidance. Please seek a health care provider for individualized health care guidance.

Reference List

  1. Shafiya Rafiqa, Rajkumari Kaula, S.A.Sofi, et al., Citrus Peel as a Source of Functional Ingredient: A Review, J Saudi Society of Ag Sci, 17;4, Oct 2018, pp 351-358, https://www.sciencedirect.com/science/article/pii/S1658077X16300960
  2. Chapter 76 – Cardiovascular Effects of Hesperidin: A Flavanone Glycoside. Polyphenols in Human Health and Disease. Vol 2, 2014, pp 989-992. https://www.sciencedirect.com/science/article/pii/B9780123984562000761
  3. Assini JM, Mulvihill EE, Huff MW. Citrus flavonoids and lipid metabolism. Curr Opin Lipidol. 2013 Feb;24(1):34-40. doi: 10.1097/MOL.0b013e32835c07fd. https://www.ncbi.nlm.nih.gov/pubmed/23254473
  4. Bobbie Randall, RD. Citrus Albedo is Better Than You Thought, Jan 22, 2020, delgazette.com, https://www.delgazette.com/opinion/81450/citrus-albedo-is-better-than-you-thought
  5. Cincin ZB, Kiran B, Baran Y, B.Cakmakoglu. Hesperidin promotes programmed cell death by downregulation of nongenomic estrogen receptor signalling pathway in endometrial cancer cells. Biomedicine & Pharmacotherapy, Vol 103, July 2018, pp 336-345 https://www.sciencedirect.com/science/article/abs/pii/S0753332217332407
  6. Hesperidin/ScienceDirect, https://www.sciencedirect.com/topics/neuroscience/hesperidin CITRUS FRUITS | Processed and Derived Products of Oranges C.M. Lanza, in Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003 // A Review of the Effects of Citrus paradisi (Grapefruit) and Its Flavonoids, Naringin, and Naringenin in Metabolic Syndrome Bibi Marjan Razavi, Hossein Hosseinzadeh, in Bioactive Food as Dietary Interventions for Diabetes (Second Edition), 2019

Citrus & Fig Marmalade Jam

Figs are also rich in quercetin (1) and pomegranate peel also contains significant amounts of the phytonutrient, (2). Quercetin can act as a zinc ionophore when zinc is present and carry the zinc into infected or cancerous cells where the zinc disrupts replication, see the last post, and Treatments vs ‘a cure’.

Orange Marmalade is a sweet jam made from citrus juice and peel. I made a modified low sugar version using the orange zest part of the orange peel that I had been removing when eating an orange with the white pith left on (see last post – it acts as a decongestant fairly quickly when eaten in that large of an amount (the whole orange with the white pith layer left on).

*This was an initial attempt and turned out too thick – just skip the jam part of the recipe if you want to simply make a fruit sauce preserve. Freeze the amount that you won’t be able to use fresh within a week or two as low sugar fruit sauces or jam are more likely to spoil – the large amount of sugar makes jams and jellies less likely to spoil. See: How does sugar act as a preservative? (sciencefocus.com) However if the goal is a way to preserve citrus peel for antiviral benefits than low sugar is going to be more supportive of immune function than a full sugar product.

— the point is not a recipe – the point is demonstrating a way to save time and preserve a large batch of outer citrus peel at once so small amounts can be used throughout the day and keep congestion cleared. Fruit preserves can be a mix as the jam package suggests and the basic ratios and which fruits might be more similar in acidity are grouped together on the instruction sheet pectin package.

*simpler way to get bioflavonoids in the diet of many people at once -add powdered citrus bioflavonoids citrus bioflavonoid powder to applesauce or yogurt or a smoothie type beverage or a breakfast porridge or soup. It is available in varied concentration. The preserved citrus jam could be used in a similar way but might be stronger in flavor than a concentrated powder.

I also had some fresh pomegranate peel on hand which I had peeled the outer more tannin rich layer from, (4), and an eight ounce package of dried figs and one pear for sweetness and to reduce the acidity somewhat.

Stevia is an herbal alternative sweetener which also has health benefits, including activation of the p53 protein, (3, also discussed in the last post), and I used a low sugar pectin mix that uses calcium to aid in gelling, Pomona’s Universal Pectin. It includes basic recipes that you can modify depending on your available fruit and sugar preferences. So without going into the specific jam details, here is a list of ingredients that I used, roughly estimating it as a double batch, however it thickened readily and I could have used pectin and calcium for one batch. (pomonapectin.com)

The cardamom powder and pomegranate peel cause the darker color, Citrus peel and fig would likely look more like a traditional orange marmalade.

Citrus Fig Savory Marmalade: Ingredient list (trial 1)

  • 2 1/2 cups minced orange peel
  • 1 1/2 cups minced inner pomegranate peel
  • 1 cup pear, peeled and minced
  • 1 1/2 cups figs, stem removed and minced, (8 ounce package dried)
  • 4 cups water
  • 1 tablespoon cardamom, powdered spice
  • 1 cup brown sugar – added to the stewing fruit, simmer gently to preserve phytonutrients, approximately 20 minutes to soften the citrus peel.
  • 6 tablespoons lime or lemon juice, bottled – for a double batch following the Pomona’s directions
  • 2 tablespoons of the calcium water solution – for a double batch
  • 1 cup Stevia sugar substitute with 1/2 cup = 1 cup sugar – measure into a separate bowl and mix in the pectin powder – to add to the fruit at the end, stir in thoroughly and let simmer for 1-2 additional minutes
  • 3 tablespoons of the Pomona’s pectin, (pomonapectin.com)

The jam cooled to a firm consistency, I could have used a single batch of lime juice, calcium water, and pectin. It made six cups which I froze most of and will keep the rest in the refrigerator as low sugar jams are more likely to mold/spoil than full sugar jam – the large amount of sugar acts as a preservative as it is too concentrated for bacteria to grow in, though mold may still occur. See: How does sugar act as a preservative? (sciencefocus.com)

The jam is mildly sweet and slightly spicy with the cardamom which also may have some antiviral and anticancer benefits by helping activate the p53 protein, which is involved in apoptosis – the killing and safe removal of infected or cancerous cells by our white blood cells. (6)

In addition to using a spoonful on toast, it is good added to a breakfast hot cereal or yogurt and would be easy to add to a cookie recipe if fresh orange peel isn’t available, see previous post: Dark Chocolate Orange Peel Cookies – Recipe.

Health can taste delicious. The taste buds will become more sensitive to the natural sweetness in foods after eating a lower sugar diet for a while.

The following is a series of jam/jelly recipes using citrus and pomegranate peel (fresh and/or dried/powdered). Both citrus and pomegranate peel have anti-inflammatory and other health benefits including antiviral properties.

The simplest way to prepare citrus peel for later use would be to mince the washed peel (collected over a few days in the refrigerator), and simmer it with water and a little brown sugar and possibly a spoonful of coconut oil or butter to help draw out fat soluble phytonutrients.

In a sauce pan bring the orange peel, 1 cup of water, 2 tablespoons of coconut oil & 1 tablespoon of stevia to a boil and remove from heat. (From Dark Chocolate Citrus peel Cookies recipe)

Citrus Plum: Ingredient list (trials 3 & 3.2)

  • 1 1/2-2 cups minced orange peel
  • 1 1/2 cups minced inner pomegranate peel and/or 6 tablespoons powdered dehydrated pomegranate, inner peel
  • 2 cups plums, minced
  • 1 cup prunes, minced,
  • 3 cups water – if more or less fresh fruit is available then adjust the water up/down to make up the difference, leaving a cup to simmer the citrus peel for a few minutes initially with the brown sugar, before adding the fresh plums and other ingredients.
  • 1-2 teaspoon cardamom, powdered spice
  • 1 cup brown sugar – added to the stewing fruit, simmer gently to preserve phytonutrients, approximately 20 minutes to soften the citrus peel.
  • 6 tablespoons lime/lemon juice, bottled, or 2 Tbs apple cider vinegar
  • 2 tablespoons of the calcium water solution – for a double batch
  • 1 cup Stevia sugar substitute with 1/2 cup = 1 cup sugar – measure into a separate bowl and mix in the pectin powder – to add to the fruit at the end, stir in thoroughly and let simmer for 1-2 additional minutes
  • 2 teaspoons of the Pomona’s pectin, (pomonapectin.com), if the 6 tablespoons of powdered dried pomegranate inner peel is used. The fresh pomegranate peel and citrus peel have pectin type fiber and less additional pectin may be needed to thicken the jam or jelly made with it, however the powdered dried peel is more thickening. Some additional pectin still seems to be needed for a full gel reaction
The fruit jam can be made into a chocolate sauce or thicker ganache that can be used as a cookie or cake filling or frosting, or be made into chocolate truffle candies.

Citrus Chocolate Ganache/Fudge sauce

Simmer one-two cups of the citrus plum jam in a double boiler, – metal bowl that fits in a sauce pan that has a couple inches of simmering hot water – and add one teaspoon of vanilla, (optional), and one tablespoon coconut oil per cup of jam, stir until it is mixed in evenly, and then add 1/4 cup cocoa powder per cup of jam, stir until the powder is all incorporated into the chocolate fudge mixture. It will be lumpy because of the fruit pieces but the chocolate sauce should mix into a chocolate-y smoothness where there isn’t fruit pieces.

Whether the mixture will be a thin or thick sauce or a frosting like ganache texture depends on the ratio of cocoa powder to liquid that you use. Pomegranate juice could be used to thin the ganache if a sauce were needed. Thicker ganache can be rolled into truffle like dessert candies, coated with cocoa powder to prevent stickiness. Store and serve chilled from the refrigerator or freezer.

Chocolate citrus peel truffles (without a solid chocolate coating added).

Pomegranate Jelly, made with powdered pomegranate peel (and violets) – ingredient list

  • 6 tablespoons powdered dehydrated pomegranate, inner peel
  • 4 cups pomegranate juice
  • 1 cup violets, (optional) rinsed and drained gently
  • 1 cup brown sugar – added to the stewing fruit,
  • 2 Tbs apple cider vinegar or lime/lemon/juice (I was making a citrus free batch for people with allergy).
  • 2 tablespoons of the calcium water solution (if using Pomona’s Pectin)-
  • 1 cup Stevia sugar substitute with 1/2 cup = 1 cup sugar – measure into a separate bowl and mix in the pectin powder – to add to the fruit at the end, stir in thoroughly and let simmer for 1-2 additional minutes
  • 2 teaspoons of the Pomona’s pectin, (pomonapectin.com), if the 6 tablespoons of powdered dried pomegranate inner peel is used. The fresh pomegranate peel and citrus peel have pectin type fiber and less additional pectin may be needed to thicken the jam or jelly made with it, however the powdered dried peel is more thickening. Some additional pectin still seems to be needed for a full gel reaction
Pomegranate Jelly, made with powdered pomegranate inner peel, and violets (peppery). It was good served hot over a vegetable salad. Jam and jelly can be used as a tangy extra along with an entree (mint jelly and lamb, cranberry gelatin with turkey, chutney with Indian meals).
Purple violets and white with purple centers. If using edible flowers for cooking or fresh avoid chemically treated lawns or flowerbeds and private property or public lands.
More violets than lawn.

*Why violets? – they contain a fragrance phytonutrients that may help protect against retinal deterioration common with aging, and increase melanin production in the skin, helping protect against skin cancer potentially. How many violets is a serving? They are peppery, I enjoy eating a a few at a time.

Reference List

  1. Brian, 93 Quercetin Rich Foods, 2 October 2018, MyIntakePro.com https://myintakepro.com/blog/quercetin-rich-foods/ via @HiperacusiaCAT
  2. X. Zhao, Z. Yuan, Y. Fang, Y. Yin, and L. Feng, Flavonols and Flavones Changes in Pomegranate (Punica granatum L.) Fruit Peel during Fruit Development. J. Agr. Sci. Tech. (2014) Vol. 16: 1649-1659, http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.1021.8526&rep=rep1&type=pdf
  3. Chen J, Xia Y, Sui X, et al. Steviol, a natural product inhibits proliferation of the gastrointestinal cancer cells intensively. Oncotarget. 2018;9(41):26299–26308. Published 2018 May 29. doi:10.18632/oncotarget.25233 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995179/
  4. J. Depew, G13. Pomegranate – Health Benefits and Preparation, effectivecare.info, https://effectivecare.info/g13-pomegranate
  5. Divya Sehgal, How does sugar act as a preservative?, sciencefocus.com, https://www.sciencefocus.com/science/how-does-sugar-act-as-a-preservative/
  6. Yu‐Jen Jou Chao‐Jung Chen Yu‐Ching Liu, et al., Quantitative phosphoproteomic analysis reveals γ‐bisabolene inducing p53‐mediated apoptosis of human oral squamous cell carcinoma via HDAC2 inhibition and ERK1/2 activation. Proteomics, 15;19, Oct 2015, pp 3296-3309, https://www.ncbi.nlm.nih.gov/pubmed/26194454

Bitter taste receptors in the lungs & Hesperidin’s decongestant properties.

How did citrus peel help my symptoms? In several ways it turns out, potentially. Antiviral actions, decongestant ability within the lungs, and by reducing the risk of blood clot formation within the lungs as the viral load increases and more tissue damage has occurred.

The antiviral capabilities were mentioned in previous posts – hesperidin and neohesperidin may act as antivirals in several ways, the vitamin C also, and quercetin can act as a zinc ionophore. Zinc ionophores are like chemical taxi-cabs – carrying zinc into infected cells preferentially where the zinc then disrupts the viral replication. (this post) No viral replication, no cell bursting to release them to infect other cells, and so on, in an exponentially increasing level of viral load and dead cells for the patient. The dead cell contents can also become a health risk when occurring in too great a quantity for white blood cells to collect it all for safe detoxification and removal at lymph nodes and by the kidneys.

Decongestant action is due to the bitterness of the hesperidin, neohesperidin, and probably other bitter tasting phytonutrients in citrus peel, and also quinine & chloroquines (also bitter tasting). (19) Think of taste or other sensory receptors that can do a variety of different things depending on where they are located and what they are connected to. Receptors are like tiny machines, activate the keyhole/puzzle piece opening with the matching chemical agonist, or inhibit with the matching chemical antagonist, and then the machine will do something if activated, or not do something or stop doing something if inhibited.

The chloroquines and quinines were found to help relax the airway in people with asthma, and increase movement of mucus out of the lungs. Activation of the bitter taste receptors on immune cells led to reduced production of inflammatory chemokines and cytokines. (19)

Taste receptors on the tongue would be connected to nerve cells that tell the brain a bitter taste or other flavor type was sensed and that information would be used to eat more if hungry for the taste or to stop eating if satisfied. Taste receptors for sweet carbohydrates are much less sensitive, more of the sweet taste is needed to activate them, than bitter taste receptors, by a magnitude of thousands – one or a few molecules of a bitter substance might activate the taste bud in the mouth, while thousands of sweet molecules might be needed to activate the sweet taste receptor. Sour is somewhere in between in the amount of sour molecules needed to activate sour taste receptors.

In other areas of the body sensory receptors may be attached to other chemical pathways instead of to nerves that go to the brain. Within the lungs there are many bitter taste receptors which when activated signal the mucus lining of the lung cells to make thinner mucus and to increase the motion of the cilia. Cilia are hair like or tail like projections lining the cell walls that can all work together in a wave like motion to move mucus and any dust or virus or other infectious microbes up and out of the lungs. (2)

Stimulation of these receptors by known bitter compounds activates calcium-dependent nitric oxide (NO) production that increases phosphorylation of ciliary proteins through protein kinase G (PKG). This increases ciliary beat frequency to facilitate the movement mucus out of the airway by increasing mucociliary transport rates. The generated NO also diffuses into the airway surface liquid & acts as an antibacterial defense mechanism. NO damages bacterial cell walls & DNA & may also damage fungal pathogens & inactivate viral proteins .” (Freund & Lee, 2)

Non-productive cough, a dry cough, feeling like something is in the lungs but you just can’t cough it out is part of the typical symptoms of COVID19/SARS-CoV2 infections for people who get sick rather than being asymptomatic carriers*. (*see footnote) To be able to have thin mucus that is protective, able to be traveled through easily by our mobile line of defense – the white blood cells, we need to have adequate water, and electrolytes (ions) within the cells: magnesium and potassium, and outside of the cells: sodium and calcium. Providing magnesium as a supplement (300 mg/day) helped thin mucus for patients with the genetic condition Cystic Firbrosis which causes chronic excess lung congestion. (16)

Mucus is more than 95% water, making water and ions just as important for controlling mucus properties .” (1)

If a person also is having nausea and vomiting and/or diarrhea, at the same time or in progressive stages, then dehydration and electrolyte deficiencies may become a significant problem, even life-threatening if severe. See this post (ACE2…) for digestive tips, and this one for a way to bypass malabsorption of magnesium with a topical source that can be absorbed through hair follicles (which is how ancient people would have gotten plenty – fresh water sources uses to be rich in magnesium).

To activate the bitter taste receptors that help with forming healthy thin mucus and help activate the wave like motion of the cilia we would need to have some bitter chemicals that match the bitter taste receptors found in great quantity within lung tissue. Hesperidin is a tasteless chemical found in citrus peel, with a bitter tasting chemical side chain, (3), and neohesperidin, a similar flavonoid, likely is obviously bitter in taste. (26)

Hesperidin, a flavonoid present in many citrus fruits, provides an example of a multi-domain compound. This molecule was found to contain eight of the substructures that form the nodes of the tree, and a selection of these are given in Figure 6. Of the eight node substructures contained within hesperidin, only one contains a significant proportion of known bitter molecules.” (3)

Anticoagulant action: The vitamin C and flavonoids in citrus peel can also help prevent blood clot formation which in more severely ill patients with COVID19 infections has been found to be part of the mortality risk. (4) Prevention is important – strengthen capillary walls to prevent microvascular damage that can lead to blood collecting and forming clots which then may block larger blood vessels and cause stroke like damage to larger areas of tissue.

More detail about this problem is available in a document with a revised Marik Protocol for treatment of ARDS with Vitamin C Infusion (and contains thiamine, vitamin B1 which may also be needed in greater quantity during a severe infection response, see this document 14, and 15). The revision recommendations are based on COVID19 treatment in China and elsewhere – the lung problems are not typical of ARDS and patients likely need more oxygen than pressure from the ventilator support or worse lung damage may result. (evms.edu/EVMS_Critical_Care_COVID-19_Protocol.pdf) (8)

Important Recommendation for Earlier Treatment for patients suspected of having a COVID19 infection – for homecare/outpatient prescriptions:

The evms.edu pdf includes a recommendation for nutrients to be used as a prevention before infection, and at home for early treatment (see the pdf for that list). Here is their recommendation for prevention dosing:

  • Vitamin C 500 mg BID and Quercetin 250-500 mg BID
  • Zinc 75-100 mg/day (acetate, gluconate or picolinate). Zinc lozenges are preferred. After 1-2 months, reduce the dose to 30-50 mg/day.
  • Melatonin (slow release): Begin with 0.3mg and increase as tolerated to 1-2 mg at night
  • Vitamin D3 1000-4000 u/day (optimal dose unknown). Likely that those with baseline low 25- OH vitamin D levels and those > living at 40o latitude will benefit the most.
  • (evms.edu/EVMS_Critical_Care_COVID-19_Protocol.pdf) (8)
  • Food sources of Quercetin include dock, sorrel, cilantro/coriander leaves, radicchio, kale, watercress, asparagus, onions, and okra: (graphic, via @HiperacusiaCAT), in addition to being found in citrus peel. (23)
  • Quercetin and EGCG are both are zinc ionophores that can carry zinc into infected cells preferentially where the zinc disrupts viral replication, and they may also have direct antiviral effects by inhibiting proteins that are important to the virus. The two phytonutrients may be even more effective at inhibiting the SARS-CoV2/COVID19 proteins than hydroxychloroquine and remsdivar medications based on computer modeling of the molecular shapes of the viral proteins, medications, and phytonutrients. (24)

Early treatment is critical due to the SARS-CoV-2 virus causing loss of iron from hemoglobin within red blood cells. In later stages of viral replication the lack of functioning hemoglobin alone causes lung damage due to the lack of oxygen. (20) Simply providing extra oxygen can’t help if there is too little functional hemoglobin. Providing blood transfusions with healthy red blood cells might be helpful – preventing the virus from replicating to that point would be better. *This theory was based on computer modeling and has not been verified. (25) The symptom of red blood cell’s having hemoglobin that is unable to transport oxygen is present in symptomatic Covid-19 illness, the theory about why iron is shifted out of hemoglobin was flawed.

Anemia of inflammation (post) could be the reason: the cytokine IL-6 causes an increase in hepcidin, which causes an increased movement of iron out of molecules of hemoglobin in red blood cells, or available for the growing red blood cells still within bone marrow, and into intracellular storage where it can overload the ability to keep it from oxidizing other chemicals and can lead to cell death. Pathogens also need iron so the strategy is a defense mechanism of the body that can become dangerous if the response becomes excessive. See the post Anemia of Chronic Inflammation, IL-6, Hepcidin, Iron, and Vitamin C, for more information.

A different group is recommending to the FDA to fast track approval for preventive, early treatment with zinc and an anti-malarial and an antibiotic that are fairly available and have a long history of use, so risks and dosing have been studied. “It’s important to note that HCQ, zinc, and azithromycin are very well understood drugs with clear safety profiles; they are widely available, generic, inexpensive, and can be scaled rapidly, including to the developing world, which would be expedited by US leadership in recommendations.” More is included in the second half of this post about the zinc and anti-malarial medication and other food/phytonutrient zinc ionophores which include quercetin. See this document for the recommendation to the FDA: (Immediate Treatment for Early Stage SARS-CoV-2 Infections). via (13)

Safety considerations of nutrient/phytonutrient Zinc Ionophore: Quercetin in very large doses may affect kidney health negatively (I can’t find a dose for that) however in an animal based study quercetin was protective of kidney health at a dose that would be about 360-720 milligrams per day for an adult weighing about 160 pounds (5-10 mg/Kg was provided to the experimental animals). (6) The amount of quercetin used as a zinc ionophore by a Canadian team may be 500 mg taken three times per day during or prior to suspected viral infection – but I can’t find the specific dosing. Zinc can be taken in larger amounts (~15-30 mg) for a few weeks but can collect in the body to excessive levels over time. Symptoms of chronic excess might include a decrease in immune function and copper deficiency may occur as the two trace minerals can affect each other (an excess of copper can cause a zinc deficiency). (Symptoms of excess Zinc, 7)

Bonus – Circadian cycles affect immune function – because bonuses are nice – another way phytonutrients, including hesperidin (9), may be helping immune function is by tipping the body towards the anti-inflammatory night-time chemistry and away from the daytime, stress response, inflammatory pathways.

And the bigger picture take-home-point from that is sleep is important for immune function and the sleep needs to have a complete blackout level of lighting for the body to be able to switch over to the anti-inflammatory action of an ancient dark night. We make more melatonin if we get some full spectrum daylight during daytime/wake hours and have complete darkness at nighttime – so a sleep eyemask or folded piece of soft clothing like a Tshirt draped over the eyes may help health. During my untested CoV-19 like illness I did have light sensitivity headaches and found sleeping or resting with a cloth over my eyes to be helpful.

Melatonin is a hormone that helps reduce inflammatory pathways that result in increased cytokines, and inflammasomes such as NLRP3 (10) which has been associated with worse prognosis for patients with COVID19. the role of NLRP3 activity in SARS-CoV (2003 strain) has been a subject of research. (12)

An animal study on oxidative damage from a type of cancer treatment: “Oral treatment with melatonin gel had a protective effect in the small intestine, which was associated with mitochondrial protection and, consequently, with a reduced inflammatory response, blunting the NF-κB/NLRP3 inflammasome signaling activation.” (10)

Phytonutrients that might inhibit NLRP3 and/or increase p53 activity.

Other phytonutrients including quercetin which is found in citrus peel, also can help inhibit production or activity of the inflammatory NLRP3 inflammasome. Sulfarophane (broccoli, etc), resveratrol (grape skins, etc), EGCG (green tea, pomegranate peel), curcumin (turmeric/curry powder), gensenoside (ginseng), emodin (aloe vera gel), mangiferin (mango) and genipin (from a fruit used as a Traditional Chinese Medicinal) are also phytonutrients that may reduce activity or production of NLRP3 inflammasomes. (17)

Increasing activity of a protein called p53 seems to help inhibit the production or activity of the NLRP3 inflammasome. Phytonutrients and nutrients that may promote p53 activity also include zinc, artemisinin (wormwood herb), goldenseal (berberine, also found in a few other herbs), Black seed oil (Nigella sativa), ginger (6-gingerol), feverfew, chamomile, and cordyceps mushrooms. (18) Replication of human coronaviruses and the SARS-CoV-1,(2003 strain) virus has been found to be inhibited by p53 and have also been found to cause the production of an additional protein that leads to breakdown of the p53 protein which may help explain the dysfunction of immune function in more severe infections. (21, 22)

Inactivating the NLRP3 inflammasome seems to have anti-inflammatory benefits (17) that may help prevent age related changes. It is an area of research being pursued for pharmaceutical development. (11) Sleep masks/pitch blackness during sleep, with the alarm clock and light leaking in the window covered, could help your body inactivate the NLRP3 inflammasome on a nightly basis with no ongoing copay. Options exist and are worth trying in an order of least toxicity risk to greater toxicity risk.

*Asymptomatic carriers: In some people the virus replicates somewhat but not to the point of much cell damage – not growing exponentially to the point of the patient’s life being threatened. Instead the virus seems to just become dormant within some cells and the person isn’t even aware they are sick – a symbiotic host/parasite relationship assures the parasite goes on living – in a living host – which is not abnormal, we typically have virus in us that can even provide some health benefits possibly – symbiotic means benefits both the host and the parasite, but not enough is known about this area of study – called our virome, (5), instead of microbiome.

Disclaimer: This information is provided for educational purposes within the guidelines of Fair Use. It is not intended to provide individual guidance. Please seek a health care provider for individualized health care guidance.

Reference List

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  20. *This paper has been found to have flaws in the interpretation. (25) Wenzhong Liu, Hualan Li, COVID-19: Attacks the 1Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism. covid19-2020004-9-EN.pdf ChemRxiv, https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173
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  25. Randy J Read, Flawed methods in“COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism” ChemRxiv.org, https://chemrxiv.org/articles/Flawed_methods_in_COVID-19_Attacks_the_1-Beta_Chain_of_Hemoglobin_and_Captures_the_Porphyrin_to_Inhibit_Human_Heme_Metabolism_/12120912
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