Anemia of Inflammation, IL-6, Hepcidin, Iron and Vitamin C.

During bacterial infections iron is shifted out of hemoglobin production and into ferritin and intracellular storage. (Iron and Anemia of Chronic Inflammation, post) If amounts of the free iron overloads the cell capacity and antioxidant capacity then cell death may result and other damage. The shift of iron involves an increase in the inflammatory cytokine IL-6 (Interleucon-6) which causes an increase in hepcidin, which causes the removal of iron from hemoglobin. (5)

Having extra antioxidants in the diet can help the body cope with the sudden increase in free iron – think of rust – iron oxidizes and the body doesn’t want rust anymore than you want it on your car. Antioxidants like vitamin A and C and bioflavonoids can all help stabilize the chemically active iron. The anti-malarial herbal extract called artemisinin may help by binding some of the excess free iron stores. (4)

ACE2 receptors are likely more prevalent in the lung cells of smokers (1) and COPD patients, (3), and people living in air pollution because it has a protective effect against lung injury. It helps decrease levels of the inflammatory cytokine IL-6. (2) Which suggests that extra vitamin C and bioflavonoids, and other nutrients may also help reduce the risk of anemia of chronic inflammation and other lung and heart risks from chronic hypoxia (low oxygen levels in the blood).

The COVID-19 illness may have a risk of sudden death due to cardiovascular problems upon relapse/reinfection (6) because of the shift in iron and resulting risk of cell death due to excess free iron. The use of iron chelators or artemisinin and continuing the use of extra antioxidants such as vitamin C and bioflavonoids might help prevent excess coagulation and reverse the shift of iron atoms from hemoglobin molecules to ferritin and free iron within cells. Infectious microbes need iron too so it is a self defense strategy that may become excessive in the case of severe COVID-19 illness.

There is more about bioflavonoids, vitamin C, and coagulation risks of SARS-CoV-2 infection in this post: Bitter Taste Receptors in the Lungs – Hesperidin’s Decongestant Properties.

Reference List

  1. SJ Brake, K Barnsley, Wenying Lu, et al., Smoking Upregulates Angiotensin-Converting Enzyme-2 Receptor: A Potential Adhesion Site for Novel Coronavirus SARS-CoV-2 (Covid-19). J. Clin. Med.20209(3), 841; https://doi.org/10.3390/jcm9030841 https://www.mdpi.com/2077-0383/9/3/841/htm
  2. Lin CI, Tsai CH, Sun YL, Hsieh WY, Lin YC, Chen CY, Lin CS. Instillation of particulate matter 2.5 induced acute lung injury and attenuated the injury recovery in ACE2 knockout mice. Int J Biol Sci 2018; 14(3):253-265. doi:10.7150/ijbs.23489. Available from http://www.ijbs.com/v14p0253.htm air pollution studies – ACE2 would be protective against ACE->IL-6 “Increased ACE levels cause the activation of AT1R by Ang II, consequently inducing the expression of the inflammatory cytokines IL-6, TNF-α and TGF-β1 [17]. ACE2 counter-regulates the effects produced by Ang II by converting Ang II to Ang-(1-7), activates Mas to repress the signaling pathways of STAT3 and extracellular signal-regulated kinases (ERK) [18], and acts as an anti-inflammatory factor [19].
  3. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19. https://erj.ersjournals.com/content/early/2020/03/26/13993003.00688-2020
  4. Inhibitory effect of novel iron chelator, 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) and green tea extract on growth of Plasmodium falciparum https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590262/Artemisinin found in the Chinese medicinal plant (Artemisia annua) binds iron to form ferric-dihydroartemisinin complex, resulting in reactive oxygen species (ROS)-mediated potent anti-malarial activity against ring and late stage of CQ-resistant P. falciparum malaria parasites [5]. “
  5. Covid-19 – Liver – iron overload – lung cascade – coagulation a forum topic on peakprosperity.com with links to research, excerpts and discussion re COVID-19 – Liver – iron overload – lung cascade – coagulation. https://www.peakprosperity.com/forum-topic/covid-19-liver-iron-overload-lung-cascade-coagulation/
  6. Jules Quartly, Exclusive: Chinese doctors say Wuhan coronavirus reinfection even deadlier. Feb 14, 2020, TaiwanNews.com, https://www.taiwannews.com.tw/en/news/3876197

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)

*addition – there is likely more hesperidin in the white pith than in the orange zest:  “The French chemist Lebreton (1828) was first to isolate hesperidin from the white inner layers of citrus peels.” (7)

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
  7. The French chemist Lebreton (1828) was first to isolate hesperidin from the white inner layers of citrus peels.” Ganesh Chandra Jagetia, T Lalrinpuii Hesperidin, A Citrus Bioflavonoid Attnuates Iron Induced Biochemical Oxidative Stress in Mouse Liver.  Biomed J Sci & Tech Res August 17, 2018  https://biomedres.us/pdfs/BJSTR.MS.ID.001602.pdf 

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