Category: antioxidants

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Zinc, cancer, and bitter taste receptors

Take home point – we need the food industry to stop taking bitter tasting, but cancer preventing phytonutrients out of our processed foods. People like bland, but that doesn’t make it good for us.

We also like sweet and protein rich foods. The crispiness on baked goods, chips, or grilled foods is a combination of sugar and protein. AGEs is an acronym for the glycated – sugar added proteins. Within our body they are associated with out of control blood sugar in diabetes and with aging. In our food supply – they taste delicious but may be cancer promoting. Acrylamide is one that has been more researched and some regulations to reduce the content in food have been passed. (10)

Extruded breakfast cereals and snack foods can have an excessive amount due to the high heat of the heated extrusion process – shaping the snack and cooking it at the same time. Both people and animals like this group of glycated proteins – sweetened protein, no wonder people & animals like it. (6) We need both calories and protein to survive, but too much of most things can become a problem.

When starchy foods are cooked at higher heat, sugar and proteins can combine into acrylamide (& other AGEs) which is delicious tasting, yet may be cancer promoting & genotoxic – harmful to our DNA. (5) “Acrylamide is a chemical that naturally forms in starchy food products during high-temperature cooking, including frying, baking, roasting and also industrial processing, at +120°C and low moisture.” (5)

The breakfast cereal industry is working on methods to remove the amino acid most linked to the formation of acrylamide; so that during the high heat processing of extruded grain based foods less acrylamide will be produced. (11) Nutritional flaw in the plan – that would also leave a lower protein breakfast cereal. Your homemade hot oatmeal or oven toasted granola would not have as much acrylamide as an extruded shaped cereal.

Podcast with more info about Advanced Glycation End Products, (AGEs) and aging: Advanced Glycation End Products. Podcast w/ Pankaj Kapahi. “What are advanced glycation end products, and why do they matter for your health?” – humanOS Radio (6)

Amino acids are the smaller units that make protein chains, many can activate bitter taste receptors.

We are still learning about taste receptors. Some amino acids are detected by sweet taste receptors. L-glutamate and l-aspartate, the potentially excitotoxic amino acids, are detected by the umami receptors, savory taste receptors (TAS1R1/TAS1R3). And many amino acids are detected by bitter taste receptors, (TAS2Rs), including “l-leucine, l-isoleucine, l-valine, l-arginine, l-methionine, l-phenylalanine, l-tyrosine, l-tryptophan, and l-histidine, exhibit a bitter taste [16]“. Vitamin B1 and B2 have been evaluated as quite bitter tasting, B3 and B6 somewhat bitter tasting, while the other B vitamins and vitamin A have been evaluated as mild. Vitamin C is sensed as sour. Taste receptors are grouped as sweet, salty, sour (acidic), bitter and umami. (12)

Bitter taste receptors are a group, and are found in various places within the body in addition to the tongue.

The bitter taste receptors are a group of approximately 25 variations (7) which include some that are responsive to a few specific bitter chemicals and others that are activated by many. Four are still unknown regarding the chemicals that activate them. (12)

“It has been shown that some TAS2Rs detect only a few bitter molecules, whereas others are broadly tuned to detect numerous bitter compounds [23]. To date, 4 TAS2Rs have been qualified as orphan receptors; that is no bitter compounds that are capable of activating them have been identified.” (12)

Bitter phytonutrients commonly found in many whole food herbs and spices may help prevent cancer, likely because bitter taste receptors are found in many areas of the body in addition to the tongue. On the tongue they are connected to nerves going to be brain and act as their name suggests – taste receptors. In the other locations of the body where they are prevalent they can perform many different actions.

The different types of bitter taste receptors are not all equally found on the tongue, many are found in greater concentration in other areas of the body. Some types may be more prevalent in some areas of the body than others. (7)

Within the intestines bitter taste receptors that are activated by bitter tasting phytonutrients signal our brain that we are satisfied now, we found enough food to eat. They also are involved with reducing insulin resistance leading to more stable blood sugar levels and less risk of glycated hemoglobin, a risk factor measured in diabetes, that is associated with aging and other health problems. Bitter phytonutrients from citrus peel bioflavonoids have been found helpful to reduce Metabolic Syndrome and improve some digestive problems. (Bitter taste receptors post)

Within the kidneys bitter taste receptors help us remove excess calcium from the circulating blood (16) which might help protect against renal disease if there is chronically too much calcium and too little magnesium available. (Kidney Appreciation Day post, see the addition)

Zinc is needed to make Bitter Taste Receptors

Background info included in the last post – we need zinc to make taste receptors for sweet, bitter or protein flavors.

Our taste receptors can also be affected by what our mother ate while she was pregnant with us. What a woman eats regularly while she is pregnant can affect her child’s taste preferences later in life. More calories from fats in mom’s typical prenatal diet can lead to there being more sweet taste receptors on the tongue for baby. “Recent research indicates that the diet of a mother could directly impact the taste buds of her offspring, affecting food preferences.” (4)

We can also adjust our taste preferences by limiting sweet foods in our diet and our taste receptors will become more sensitive to sweet tastes, or by eating more bitter tasting foods we can become more used to the bitter flavors – acquiring a taste preference for some. Too much would signal we are satisfied.

Deficiency of both zinc and bitter taste receptors is associated with breast cancer cells.

Receptors are like specialized machines on the outside of cells which interact with the interior of the cell, telling it what might be going on in the surrounding extracellular fluid – are we hungry or well fed? Do we need to get a jacket because it feels cold? Is there a lack of bitter nutrients and we feel sick so we should forage for that herb that seemed to be so satisfying and helpful the last time I felt this way?

Yet we need adequate zinc in order to be able to make taste receptors. Zinc deficiency is linked to breast cancer. (1) One of the odd places where bitter taste receptors are located is the mammary tissue – milk producing cells within the breasts. It has been found that breast cancer cells have fewer bitter taste receptors on their membrane surface than cells of healthy breast tissue. (2) Zinc deficiency leads to a lack of the mRNA that is needed within a cell for it to make the specific protein that forms a taste or odor receptor. Surface receptors are made within the cell and relocated to the cell membrane.

What does the bitter taste receptor do for the mammary tissue that helps protect it against cancer? They may be promoting anti-inflammatory pathways and chemicals that help identify damaged DNA or cells and remove them safely before they start to grow into a tumorous cell.

Many plant nutrients are found to help protect against cancer, (3), but also, probably not coincidentally, are bitter in taste, so the food industry has been removing them from processed food in order to increase consumer appeal. “Dietary phytonutrients found in vegetables and fruit appear to lower the risk of cancer and cardiovascular disease.” (3)

Protection against low oxygen, hypoxia, and oxidative stress reduction may also be part of the anti-cancer benefit provided by bitter taste receptors.

Retinoic acid, a metabolite of vitamin A caused an increase in the bitter taste receptors on pre-cancerous neuroblastoma (NB) cells. NB cells are immature brain cells that contain cancer stem cells and generally only causes cancer in early infancy and childhood. Having more bitter taste receptors led to fewer tumorous cells forming from the NB cells treated with retinoic acid, and there was also a reduction in the movement of the cells which would help prevent spread of cancer. (7)

The presence of more bitter taste receptors was found to help reduce risk of cancer metastasis, the migration to other areas of the body and invasion of other tissue areas. Increased metastasis/movement of cancer cells may be more of a risk in the presence of low oxygen levels, hypoxia. Hypoxia has been linked to increased movement of cancer cells. (7) (Hypoxia is also a problem in symptomatic COVID19).

“Furthermore, expressions levels of HIF-1α-downstream genes were affected, with VEGF and GLUT1 up-regulated under CoCl2-induced hypoxic conditions, and the same genes were down-regulated following over-expression of TAS2R8 and TAS2R10 (Fig 6B). These results suggest that TAS2Rs contribute to the regulation of hypoxia-related gene expression.” (7)

The increase in bitter taste receptors and suppression of metastasis may have been due to a reduction in an enzyme MMP-2 which breaks down extra cellular matrix (the gelatinous fluid, or glycocalyx that surrounds all of our blood vessels and other organs, and fills spaces in between). Increased MMP-2 and less extra cellular matrix protection allows more invasive metastasis of cancer cells. (7)

Matrix metalloproteinases (MMPs) are a group of 23 enzymes involved in extra cellular matrix and are dependent on adequate zinc availability. They also are involved with “control of expression and activation of chemokines, growth factors, and cellular receptors,” and therefore have a role in normal development, and in inflammatory diseases and cancer. (14)

Zinc has antioxidant properties and deficiency of the trace mineral is associated with increased oxidative stress and decreased MMPs which may increase risk for excess collagen and development of fibrosis – scar tissue like formation in the areas of inflammation. (15)

Within the lungs bitter taste receptors can help thin mucus (extra cellular matrix), cause increased motion of the cilia lining airways to move it up and out of the lungs, through more opened airways – provided we include bitter tasting nutrients in our diet. (Bitter taste receptors post)

Phytonutrients that have been shown to have anti-cancer benefits and activate certain bitter taste receptors include allyl isothiocyanate, (7) , an organosulfur found in mustard, radish, horseradish, wasabi, and other cruciferous vegetables. (13) Quercetin and naringenin, found in citrus peel and other plant foods, have also been found to provide anti-cancer benefits against several types of cancer including NB cells “[24, 26, 27].” (7)

Are AGEs always bad? – confusingly, no. Some may activate, some may inhibit bitter taste receptors.

AGEs may activate or inhibit Bitter taste receptors too, throughout the body, depending on the type of glycated protein (AGE-Advanced Glycation End-Products) which may be why some are aging & cancer promoting but not all, or not always.

AGEs may be cancer promoting in some cases but not others because of their roles as bitter taste receptor (T2R) ligands – some AGEs may activate, while others may inhibit bitter taste receptors -“In this study, we identified AGEs as novel T2R ligands that caused either activation or inhibition of different T2Rs.” (8) “Bitter taste receptors (T2Rs) are expressed in several tissues of the body and are involved in a variety of roles apart from bitter taste perception.” (8)

So the sweetened protein, potentially bitter taste of acrylamide may be inhibiting or possibly activating bitter taste receptors found in different areas of the body in ways that may affect cancer risks.

Coffee, has a varying amount of acrylamide depending on how it is prepared. Overall the beneficial antioxidants and other phytonutrients seem to give an anti-cancer effect to coffee, rather than being cancer promoting due to the acrylamide. The Coffee Acrylamide Apparent Paradox: An Example of Why the Health Impact of a Specific Compound in a Complex Mixture Should Not Be Evaluated in Isolation (9)

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

Reference List

  1. Kaczmarek K, Jakubowska A, Sukiennicki G, et al. Zinc and breast cancer risk. Hered Cancer Clin Pract. 2012;10(Suppl 4):A6. Published 2012 Dec 10. doi:10.1186/1897-4287-10-S4-A6 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518236/
  2. Dupre, D.J., Martin, L. and Nachtigal, M. (2017), Expression and Functionality of Bitter Taste Receptors in Ovarian and Prostate Cancer. The FASEB Journal, 31: 992.2-992.2. doi:10.1096/fasebj.31.1_supplement.992.2 https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.31.1_supplement.992.2
  3. Adam Drewnowski, Carmen Gomez-Carneros, Bitter taste, phytonutrients, and the consumer: a review, The American Journal of Clinical Nutrition, Volume 72, Issue 6, December 2000, Pages 1424–1435, https://doi.org/10.1093/ajcn/72.6.1424 https://academic.oup.com/ajcn/article/72/6/1424/4729430
  4. Mother’s diet may affect child’s taste buds, https://www.newfoodmagazine.com/news/120313/mothers-diet-may-affect-childs-taste-buds/
  5. Acrylamide, efsa.europa.eu, https://www.efsa.europa.eu/en/topics/topic/acrylamide
  6. Ginny Robards, The Role of Advanced Glycation End Products in Aging and Disease. Podcast with Pankaj Kapahi. Sept 18, 2019, blog.humanOS.me, https://blog.humanos.me/advanced-glycation-end-products-aging-disease-podcast-pankaj-kapahi/ via Tweet by https://twitter.com/humanOS_me/status/1316517757152751616?s=20
  7. Seo Y, Kim YS, Lee KE, Park TH, Kim Y. Anti-cancer stemness and anti-invasive activity of bitter taste receptors, TAS2R8 and TAS2R10, in human neuroblastoma cells. PLoS One. 2017;12(5):e0176851. Published 2017 May 3. doi:10.1371/journal.pone.0176851 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414998/
  8. Jaggupilli A, Howard R, Aluko RE, Chelikani P. Advanced Glycation End-Products Can Activate or Block Bitter Taste Receptors. Nutrients. 2019;11(6):1317. Published 2019 Jun 12. doi:10.3390/nu11061317 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628017/
  9. Astrid Nehlig and Rodrigo A. Cunha, The Coffee–Acrylamide Apparent Paradox: An Example of Why the Health Impact of a Specific Compound in a Complex Mixture Should Not Be Evaluated in Isolation. Nutrients. 2020 , 12, 3141; doi:10.3390/nu12103141 Published 14 October 2020 https://res.mdpi.com/d_attachment/nutrients/nutrients-12-03141/article_deploy/nutrients-12-03141.pdf via Tweet by https://twitter.com/HealthyFellow/status/1316442214440943616?s=20
  10. David Acheson of The Acheson Group, FDA Issues Guidance on Reducing Acrylamide. May 31, 2016, foodprocessing.com, https://www.foodprocessing.com/articles/2016/fda-issues-guidance-on-reducing-acrylamide/
  11. E. J. M. Konings, P. Ashby, C. G. Hamlet & G. A. K. Thompson (2007) Acrylamide in cereal and cereal products: A review on progress in level reduction, Food Additives & Contaminants, 24:sup1, 47-59, DOI: 10.1080/02652030701242566 https://www.tandfonline.com/doi/abs/10.1080/02652030701242566?mobileUi=0&journalCode=tfac19
  12. Delompré T, Guichard E, Briand L, Salles C. Taste Perception of Nutrients Found in Nutritional Supplements: A Review. Nutrients 2019, 11(9), 2050; https://doi.org/10.3390/nu11092050 https://www.mdpi.com/2072-6643/11/9/2050/htm
  13. Zhang Y. Allyl isothiocyanate as a cancer chemopreventive phytochemical. Mol Nutr Food Res. 2010;54(1):127-135. doi:10.1002/mnfr.200900323 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814364/
  14. Xu X, Wang Y, Chen Z, Sternlicht MD, Hidalgo M, Steffensen B. Matrix metalloproteinase-2 contributes to cancer cell migration on collagen. Cancer Res. 2005 Jan 1;65(1):130-6. PMID: 15665288. https://cancerres.aacrjournals.org/content/65/1/130.long
  15. Cao, J., Duan, S., Zhang, H. et al. Zinc Deficiency Promoted Fibrosis via ROS and TIMP/MMPs in the Myocardium of Mice. Biol Trace Elem Res196, 145–152 (2020). https://doi.org/10.1007/s12011-019-01902-4 https://link.springer.com/article/10.1007/s12011-019-01902-4
  16. Liang J, Chen F, Gu F, Liu X, Li F, Du D. Expression and functional activity of bitter taste receptors in primary renal tubular epithelial cells and M-1 cells. Mol Cell Biochem. 2017 Apr;428(1-2):193-202. doi: 10.1007/s11010-016-2929-1. Epub 2017 Feb 24. PMID: 28236092. https://pubmed.ncbi.nlm.nih.gov/28236092/


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Cytokine Storm, SIDS, autism and Vitamin C

The over-reaction of the immune system to any infectious stimulant whether an infection or vaccines, may be a cause of Sudden Infant Death Syndrome (SIDS) (1) and the encephalopathy (2) that is a frequent factor in later development of autism. (3)

Sudden Infant Death Syndrome may be a toxin overload as success was achieved with mattress covers in Australia that prevented volatile chemicals or mold spores from reaching the baby. Crib mattresses often contain vinyl or fire retardants and a used mattress likely has mold even if not obvious. It can be healthy for infants to sleep on their belly as helps with even muscle development and skull shape. Babies that are held or left in the same position all the time can development flattened areas on the skull and limit muscle development. See previous post1, post2, post3.

Giving infants and children vitamin C prior to vaccines orally with juice may be protective against the harmful excess production of inflammatory cytokines. Giving a larger amount intravenously for adverse reactions may also be protective against the cytokine overreaction from worsening as the larger amount of vitamin C has an inhibitory effect on the production of them as well as helping as an antioxidant to detoxify the ones already made in excess. Giving extra vitamin C before vaccines was found to be protective even in lab animals that genetically can make vitamin C. (4)

Cytokine Storm over-reactions may be more of a risk due to genetic differences in as many as 10-15% of the population. (5) Symptoms of a Cytokine Storm reaction can include: “high fever, enlarged spleen, excessive bleeding, low counts of all types of blood cells (red, white and platelets) and, potentially, multiple organ failures.” (5) Diarrhea is unpleasant and can kill if it continues for long however multiple organ failures is more deadly.

Providing vitamin C as a protection against the risk of an overreaction of the immune system would be low cost and has had a low risk of side effects. Diarrhea occurs if excess is taken by mouth so there is little risk of too much being absorbed in the GI tract, and adverse reactions to higher doses of vitamin C given as intravenous therapy have not been prevalent (1%) in studies using the treatment as an addition to chemotherapy treatments. (6)

“Phase I studies of IV C alone & in combination with chemotherapy have reported excellent safety profiles 1–8,33. A survey of providers who used IVC for 9328 patients reported an adverse event rate of 1.0% 68..side effects of IVC…nausea, dizziness, dry mouth, perspiration, & weakness. 6,7” (6)

Giving vitamin C to infants and children would be providing them with a nutrient than most animals can produce for themselves. Humans had a genetic change that caused a loss of the ability. Giving vitamin C to infants and children might also help protect against a potentially fatal or brain damaging over-reaction of the immune system. If 10-15% of the population are genetically more at risk for the excess production of cytokines, (5) , then a government policy that mandates vaccinations would be genetically targeting those individuals for increased risk of an adverse reaction or death – a genocide.

Learning more about the gene differences involved in the increased risk for a Cytokine Storm reaction, and screening the population for the genes would also be helpful so those individuals would know that they have increased risk of death if they have an infection or strong immune reaction to something.

The Committee  to Review Adverse Effects of Vaccines that was asked to assess the research on autism and vaccines did not say there was no risk of autism from vaccines – they said there was a lack of evidence – more research was needed.

“The committee particularly counsels readers not to interpret a conclusion of inadequate data to accept or reject causation as evidence either that causation is either present or absent. Inadequate data to accept or reject causation means just that—inadequate. It is also important to recognize what our task was not. We were not charged with assessing the benefits of vaccines, with weighing benefits and costs, or with deciding how, when, and to whom vaccines should be administered.“

Committee to Review Adverse Effects of Vaccines
Board on Population Health and Public Health Practice, Institute of Medicine (7)

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. Siri Hauge Opdal, PhD., Chapter 30: Cytokines, Infection, and Immunity, from the book SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future. Duncan JR, Byard RW, editors., Adelaide (AU): University of Adelaide Press; 2018 May. https://www.ncbi.nlm.nih.gov/books/NBK513388/
  2. Cytokine Storm, ScienceDirect.com, https://www.sciencedirect.com/topics/medicine-and-dentistry/cytokine-storm
  3. Kern JK, Geier DA, Homme KG, Geier MR. A ten year longitudinal examination of the incidence rate and age of childhood encephalopathy diagnoses in an autism spectrum disorder diagnosed cohort. Acta Neurobiol Exp (Wars). 2020;80(1):66–75. https://pubmed.ncbi.nlm.nih.gov/32214276/
  4. C. Alan B. Clemetson, M.D., Rapid Response: The prevention of vaccine reactions. BMJ 2004;328:51 https://www.bmj.com/rapid-response/2011/10/30/prevention-vaccine-reactions
  5. University of Alabama at Birmingham, Here’s a playbook for stopping deadly cytokine storm syndrome. Nov 11, 2019, theivcenter.net, https://theivcenter.net/wp-content/uploads/2018/05/Vit-C-and-Cancer-Support.pdf
  6. E. Klimant, H. Wright, D. Rubin, et al, Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach. Curr Oncol. 2018 April;25(2):139-148, https://theivcenter.net/wp-content/uploads/2018/05/Vit-C-and-Cancer-Support.pdf
  7. Institute of Medicine (U.S.). Committee to Review Adverse Effects of Vaccines.  Adverse effects of vaccines : evidence and causality / Committee to Review Adverse Effects of Vaccines, Board on Population Health & Public Health Practice ; Kathleen Stratton … [et al.], eds.  ISBN 978-0-309-21436-0 (PDF)  https://www.nap.edu/read/13164/chapter/1
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Nrf2 and Nf-Kb pathways – one restorative, one inflammatory

Many phytonutrients and other chemicals have been found to promote the production of the Nrf2 gene and its encoded Nrf2 protein, both of which have varying impacts on other genes causing an increase in immune strength and in our own production of antioxidants. Other research has focused on nutrients and chemicals that inhibit or promote the inflammatory Nf-Kb pathway – a chemical cascade of reactions starting outside the cell and ending in the cell with an increase in the cell’s production of inflammatory cytokines and Tumor Necrosis Factor (TNF).

The foods and chemicals often interact with both pathways but in opposite directions, promoting one and inhibiting the other. The reason is unlikely to be a coincidence, the night/day rhythms of circadian biology also tend to promote one and inhibit the other. The Nrf2 growth/repair/detoxification system is more active during sleep/dark and the NF-kB action/inflammation pathway is more active during the wake/light hours. See 1.4, 1.41, 1.42 in this draft book to read more: Preventative Health for Multifactorial Disorders.

Nrf2 Promoting Foods & Phytonutrients:

See G10: Nrf2 Promoting Foods, effectivecare.info for the reference in the graphic (Sun 2017) and more food ideas and information.

Nrf2 Promoting Foods and Phytonutrients

Neurotransmitters also vary in activity level due to the circadian cycle and can affect whether the Nrf2 or the NF-kB pathway is more active.

The neurotransmitters and neuromodulators mentioned in the last post are part of the circadian biology rhythms. Acetylcholine, attention and memory neurotransmitter, (Pepuo 2004), is more active during the day and GABA the calming neurotransmitter is more active at night. It is inhibitory, reducing activity of other neurotransmitters such as norepinephrine and serotonin that are active during wakefulness helps the body move into sleep. Low levels of GABA are associated with insomnia and disrupted sleep (Siegel 2004), and with anxiety, chronic stress, depression, difficulty concentrating and memory problems, muscle pain and headaches, and substance use disorders. (3 AmazingBenefits of GABA/PsychologyToday)

GABA which is known to have antioxidant and anti-inflammatory benefits may achieve it in part due to increasing the Nrf2 pathways growth, repair, and detoxification activity and by inhibiting the NF-kB and Caspase 3 pathways. (Zhu 2019) Resveratrol was found to help protect endothelial cells in animal models of Type 2 Diabetes and aging. It reduces oxidative stress by increasing the Nrf2 pathways, “improves acetylcholine-induced vasodilation, and inhibits apoptosis (assessed by measuring Caspase 3 activity and DNA fragmentation). (Ungvari 2010)

Lycopene is a phytonutrient that can help reduce inflammation by promoting the Nrf2 and inhibiting the NF-kB pathways.

The antioxidant lycopene was used in a study for use as a food additive in animal feed to help reduce oxidative stress caused by heat stress. The research team were concerned about the negative effects of heat stress on the Nrf2 and Nf-Kb pathways, causing decreased activity of the Nrf2 and increased activity of the Nf-Kb pathway. A brief description of the roles in the body is in the abstract: “The transcription entity nuclear factor-kappa light chain enhancer of B cells (NF-κB) controls the expression of genes involved in a number of physiological responses, including immune inflammatory responses, acute-phase inflammatory responses, oxidative stress responses, cell adhesion, differentiation, and apoptosis. The nuclear factor-2 erythroid related factor-2 (Nrf2), the redox-sensitive transcription factor, plays a key role in regulating induction of phase II detoxifying or antioxidant enzymes.  “ (1)

Several carotenoids in addition to lycopene also reduce inflammatory pathways and increase beneficial ones.

Lycopene is a carotenoid, one of a group of red and yellow colored antioxidants found in carrots, cantaloupe and other fruits and vegetables that tend to be orange or red in color, The best known carotenoid is beta-carotene, a form of vitamin A that is made with two of the vitamin A retinol molecules. Other carotenoids, including beta-carotene, lutein, alpha-cryptoxanthin, and zeaxanthin, also can inhibit the NF-kB pathway and increase the Nrf2 pathways, reducing inflammatory cytokine production and increasing beneficial antioxidant production. Other phytonutrients that also increase the Nrf2 and inhibit the NF-kB pathways include:

Other phytonutrients that inhibit inflammatory and promote anti-inflammatory pathways:

  • sulforaphanes and I-3-C, from broccoli sprouts, broccoli, kale, mustard greens, turnips and other cruciferous vegetables,
  • andrographolides (and other diterpenoids – found in Gingko biloba, sage, rosemary, (sciencedirect/diterpenoids)), andrographolides are found in the medicinal plant Andrographis paniculata, (Okhuaroba 2014),
  • quercetin found in “leafy vegetables, broccoli, red onions, peppers, apples, grapes, black tea, green tea, red wine, and some fruit juices“, (integrativepro.com) ,
  • curcumin from turmeric,
  • silymarin, an extract from milk thistle, a medicinal herb,
  • genistein from soy,
  • chlorophyll, the green pigment in plants, and
  • resveratrol, found in “grapes, wine, grape juice, peanuts, cocoa, and berries of Vaccinium species, including blueberries, bilberries, and cranberries.” (lpi.oregonstate.edu)
  • (See 1.42, Preventative Health for Multifactorial Diseases)

That list is a start, there are other beneficial phytonutrients that decrease inflammatory pathways and increase anti-inflammatory pathways, including: ginger/zerumbone/gingerol, green tea/EGCG/gallic acid, garlic/aged garlic extract, hot pepper/capsaicin, fish oil/omega 3 fatty acids, black pepper/piperine, Hops/xanthohumol, Plumbago auriculata/plumbagin, a medicinal herb used for lead poisoning. (de Paiva 2005) (Sun 2017) (Gupta 2010)

Protecting health over the long term and every day can be as simple as adding more variety of herbs and spices to your meals, along with more colorful fruits and vegetables and whole grains, nuts, beans, and seeds.

That list is a start, there are other beneficial phytonutrients that decrease inflammatory pathways and increase anti-inflammatory pathways, including: ginger/zerumbone/gingerol, green tea/EGCG/gallic acid, garlic/aged garlic extract, hot pepper/capsaicin, fish oil/omega 3 fatty acids, black pepper/piperine, Hops/xanthohumol, Plumbago auriculata/plumbagin, a medicinal herb used for lead poisoning. (de Paiva 2005) (Sun 2017) (Gupta 2010)

Protecting health over the long term and every day can be as simple as adding more variety of herbs and spices to your meals, along with more colorful fruits and vegetables and whole grains, nuts, beans, and seeds.

Colorful and flavorful foods can help keep the body more in the restorative Nrf2 pathways and reduce the inflammatory NF-kB pathway. The same nutrients or chemical groups effect both because the pathways are coordinated by the light/dark wake/sleep circadian cycle and share a need for the same type of protein – as if both need the same tool – they both can’t use it exactly at the same time. (CREB protein, see section 6: Li, 2008)

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

References

  1. Sahin K, Modulation of NF-κB and Nrf2 pathways by lycopene supplementation in heat-stressed poultry, World’s Poultry Sci J Vol 71, Issue 2, June 2015 , pp. 271-284 https://www.cambridge.org/core/journals/world-s-poultry-science-journal/article/modulation-of-nfb-and-nrf2-pathways-by-lycopene-supplementation-in-heatstressed-poultry/4E2AFAAFDF88B0B438BE3A19A1FB0A9B
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Hypercoaguability; TNF alpha & Nrf2

*This post got quite long so I put it in a document form too and added a Table of the medicinal foods/herbs/extracts, there are still more to add: docs.google.com . The table of 700 small molecules that may help reduce TNF-alpha by inhibiting the NF-kB pathway is quite large, so I am working on recreating it in list format – work in progress: docs.gogle.com/list of NF-kB pathway inhibitors.

Localized hyercoaguability & granulomatous sarcoidosis.

People with the autoimmune disease called sarcoidosis may develop increased risk of clotting, hypercoaguability, localized to the areas where the disease process progressed to the granulomatous stage. The reason is not known per the research team, Goljan-Geremek et al., as other typical cardiovascular disease markers were not commonly found in sarcoidosis patients who developed venous thromboembolism (VTE). (1)

The problem of increased coaguability was only seen in patients with Stage II or Stage III granulomatous sarcoidosis and was associated with increased levels of “the proinflammatory cytokine cascade [interleukin (IL)-6, IL-8, tumor necrosis factor α (TNF-α) but not with IL-10 [25].” Interleukin 10 is an anti-inflammatory cytokine with a protective effect while Interleukin 6 and 8 are pro-inflammatory. Better understanding of the mechanism would be helpful as localized hypercoaguability may increase risk of pulmonary embolism or other ischemic strokes. (1)

Calcium excess, magnesium deficiency and hypercoaguability.

Magnesium and calcium balance can be involved in blood clotting risks as excess calcium can lead to blood vessel and soft tissue calcification. Vascular calcium plaques can increase risk of blood clots and excess calcium levels can also be a cause of blood clotting – hypercoaguability. (41) (42) Zinc deficiency is mentioned later in this article as a potential cause of hypercoaguability, however several key nutrients may be deficient or in imbalance during cardiovascular disease. Myocardium tissue changes structure and chemical composition during vascular or heart disease. Magnesium was found to be low while calcium levels were elevated. Vitamin D was low, the active hormone form of vitamin D was not measured. Zinc and selenium levels were found to be low. (44)

Vitamin D is involved in calcium and magnesium balance and is anti-inflammatory due to inhibition of the NF-kB pathway. Low levels of vitamin D have been associated with kidney and cardiovascular disease. (45) Curcumin, an analogue of the active hormone D form (1, 25, dihydroxy D), also inhibits the NF-kB pathway and may also be protective against renal or vascular disease. (See Table 1, 11)

The B vitamins, folate, vitamin B6 and B12, are needed for homocysteine metabolism, elevated levels of which are associated with cardiovascular disease, however reducing levels of homocysteine has not reduced thrombotic risk (clotting). (46) The importance of homocysteine may have more to do with its later chemical conversion to the potent antioxidant glutathione. (47) We make more antioxidants everyday during health than we are ever likely to consume from typical foods. Many medicinal herbs or nutrients help promote the antioxidant promoting Nrf2 pathways and inhibit the inflammatory NF-kB pathway. Vitamin B6 can also inhibit the inflammatory NF-kB pathway. (See Table 1, 11)

The nutrients could be thought of as similar to a baseball team – you might be able to play a game without the shortstop or with someone in left field however trying to play without the pitcher or catcher wouldn’t really work at all.

TNF alpha and the NF-kB Pathway

The mechanism for localized hypercoaguability in granulomatous sarcoidosis may be due to the localized increase in Tumor Necrosis Factor alpha (TNF alpha) and interleukin-6 (IL-6) which can cause “microvascular damage leading to thrombosis,” and “ischemia.” Supplementation with flavonoids can block this from occurring by inhibiting an earlier step in the intracellular pathway by preventing the stimulation of the IKK complex and the translocation of NF-κB into the cell nucleus where the pro-inflammatory cytokines are made. (See Figure 1: 2)

Deficiency in Nrf2 may cause an increase in TNF alpha as the protein inhibits production of the Tumor Necrosis Factor alpha protein by the inhibitory effect internally produced antioxidants (Nitric Oxide or glutathione for example, 11) have on the NFkB pathway. (7) And when levels of TNF alpha are elevated production of more Nrf2 is suppressed by the TNF alpha/NFkB pathway (7), which would then further exacerbate the elevated level of it as the inhibition by the Nrf2 protein would be lacking and the presence of increased levels of TNF alpha and other cytokines increases activity of the NF-kB pathway. (7)

An experimental stage chemoprevention drug beta-naphthoflavone helps protect against lung damage in mice deficient in the ability to make Nrf2. (3) Beta-naphthoflavone is an AhR agonist and antioxidant that is only approved for research purposes in animal studies currently. (4) Nrf2 has a protective role within the lungs as seen in a different animal study with Nrf2 deficient mice (knockout mice genetically deficient in Nrf2 -/- ). (5)

Flavones are a type of Flavonoid

Flavones are in the flavonoid family of phytonutrients. Flavonoids as a group are commonly found in many “fruits, vegetables, barks, stems, roots, flowers, tea, and wine.” (6) There are about 6000 flavonoids known within plants and they frequently are colorful pigments within the flowers or other parts of plants where they protect against UV light damage along with other protective roles. (6)

Therapeutically flavonoids are very beneficial for humans also, as they not only are strong antioxidants they also have “anti-inflammatory, anti-mutagenic and anti-carcinogenic properties,” can “modulate key cellular enzyme function,” and are “potent inhibitors for several enzymes, such as xanthine oxidase (XO), cyclo-oxygenase (COX), lipoxygenase and phosphoinositide 3-kinase, (4–6).” (6) Flavonoids may help protect against Coronary Heart Disease (CHD) and reduce mortality rate due to cardiovascular disease.

Onions and Green Tea – ECGC

Flavones are particularly strong antioxidants within the group of flavonoids and onions and tea are good dietary sources. (6) Green or Black tea are good sources of the flavonoid called Epigallocatechin-3-gallate (EGCG) which is known to inhibit the NF-kB pathway. (11, 12) Green and black tea are from the same type of plant however the processing is different. Green tea is simply dried fresh tea leaves and provides about four times more EGCG than black tea (which does have other healthy phytonutrients too). Patient studies suggest that heart health benefits may occur with use of three to five cups of green tea per day, which would provide about 200-350 milligrams EGCG. Bottled teas and supplements may not provide as much as labels suggest while also costing more than loose leaf tea or boxed tea bags. (17)

Orange Zest – Tangeritin

Flavones may help reduce the risk of upper respiratory infections by stimulating taste receptors that detect bitter flavors which then increase cellular production of Nitric oxide (NO) which has antibacterial effects (lethal to bacteria at higher doses). The outer zest of orange peel is a source of a flavone called tangeritin. (10)

Vinpocetine

Flavones therefore, as flavonoids, may be beneficial for Nrf2 levels by reducing the NF-kB pathway by effects on the IKK complex. (See Figure 1: 2) Steroids and cyclooxygenase inhibitors (COX1 & 2 are inhibited by many common pain relievers) are potent anti-inflammatories that also can have significant side effects. Vinpocetine is an anti-inflammatory derived from an alkaloid which has been found helpful for vascular conditions. It also reduces NF-kB activity by inhibiting the IKK complex. (8) Vinpocetine is available as an over the counter supplement singly or may be included in mixed products, and is not advised for use by pregnant people or women of childbearing age due to a possible increased risk of miscarriage according to a recent warning by the FDA. (9) Excess Nf-kB activity leading to increased levels of TNF alpha can also cause miscarriage (spontaneous abortion/fetal death). (See Figure 1: 2)

Long term steroid use may also increase coagulation risk.

An additional factor in risk for hypercoaguability in autoimmune patients such as those with sarcoidosis may be long term use of glucocorticosteroids or other long term steroid/testosterone use. Long term steroid use has been observed to increase risk of clotting, hypercoaguability, in patients with Inflammatory Bowel Disease, (13), and in bodybuilders using steroids. (14, 15)

Steroids reduce Nf-kB activity within the short term and the increased risk of coagulation for bodybuilders using anabolic-androgenic steroids (AS) is thought to be due to a combination of the strain of lifting heavy weights combined with the AAS causing changes in blood platelets and clotting factors along with impaired ability to break down clots: “AAS are responsible for a number of haemostatic defects, including higher platelet number, enhanced platelet aggregation, increased synthesis of procoagulant factors and impaired fibrinolysis.” (15)

The granulomas found in Stage II or III sarcoidosis are typically found in the lungs but may also develop in other areas of the body including in decreasing order of frequency the: “skin, eyes, musculoskeletal system, nervous system, heart, liver, and kidneys.” (16)

Dehydration

Dehydration can also be a risk factor for increased coagulation – with a lack of water how can the blood flow through any blood vessel or organ as well?

Metal implants & medical devices can also activate the NF-kB pathway.

Metal supports for broken bones or missing bone pieces and other types of metal medical devices that are implanted within the body can be a source of metal exposure or infectious risk from pathogen growth on the surface of the device. Finishing the surface layer of the metal with a nanoparticle size rough texture has been found to interfere with the ability of bacterial pathogens to grow on the surface in comparison to a typically smooth metal surface. Gradual corrosion of the metal over time may remain a problem though and the metallic ions within the body can cause an increase in inflammatory TNF alpha and interleukin cytokines due to activating the NF-kB pathway.

The increased inflammation can increase osteoporosis risk due to increases in the activity of osteoclasts which absorb bone and decrease activity of osteoblasts which deposit more bone matrix. See Figure 16.4, page 267, Trace Metals and Infectious Disease, (link). Reducing the risk of corrosion of the metal implants is desirable as patients with osteoporosis often require metal supports for repair of fractures and then may be at risk of further inflammatory loss of bone due to the TNF alpha and other cytokines. The presence of a metal medical device could also then be a risk for hypercoaguability and ischemic stroke.

Zinc Deficiency can also lead to increased TNF alpha and IL – 1 beta.

Lack of the essential trace metal zinc as a chronic deficiency may add to inflammation and hypercoaguability risks due to epigenetic changes that promote production of the TNF alpha gene and protein and Interleukin 1 beta. The precise mechanism is not known and also involves redox-dependent mechanisms. Supplementation of zinc may be helpful for patients with inflammatory conditions. (Wessels et al, 2013)   (page 291, Trace Metals and Infectious Disease, link) Acute zinc deficiency in an animal based study was associated with more severe reperfusion-injury after myocardial ischaemia (heart attack) in the animals. (43)

Take Home Points

Patients with sarcoidosis may help reduce their risk for clots and ischemic stroke due to localized hypercoaguability occurring within areas of their bodies where granulomas have formed by:

  • maintaining adequate intake of water or other non-diuretic fluids.
  • avoiding long term use of glucocorticosteroids or anabolic-androgenic steroids.
  • increasing intake of onions, green tea, orange zest, (for flavone content)
  • and increasing intake of other Nrf2 promoting foods (other types of phytonutrients in addition to flavones can help the body increase production of the Nrf2 protein which helps increase production of antioxidants such as glutathione and Nitric oxide. Phytonutrients, foods and beverages that may help are available here: Nrf2 Promoting Foods).
  • Adequate protein intake is important for the body to be able to produce Nrf2 proteins, anticlotting factors, and other proteins essential for fluid balance.
  • Histidine and betaine are amino acids found within protein foods which may help inhibit the NF-kB pathway (11) which leads to increased levels of TNF alpha and interleukins which can cause increased coagulation/increased clotting risk. Betaine is formed from the amino acid glycine with three methyl groups and is also called trimethylglycine (TMG). The grain quinoa is a good source of betaine.
  • Adequate zinc in balance with copper intake is important.
  • Adequate magnesium, in balance with calcium and vitamin D is important. Selenium intake in adequate amounts may also be protective.
  • Phytonutrients and other medicinal chemicals may help reduce the inflammatory pathway. Increasing use of the food sources within the daily diet may be helpful to reduce hypercoaguability risk. Excess use of some of the more potent sources would not be advised as the blood thinning effects may be cumulative. Over 700 small molecules have been identified that inhibit the NF-kB pathway (See Table 1: 11) including: the omega 3 fatty acid DHA found in fatty fish such as salmon and sardines and Fish Oil supplements or bottled Krill or Fish oil; the herbal supplement extracts of kava and licorice; 6-gingerol found in ginger, (500 mg ginger in capsule was found as effective for pain relief as ibuprofen in a post dental surgery pain study, (26), 500-1000 mg per day was found effective for pain relief in a metareview of studies on arthritis pain, (27), Ginger was found to be more effective than ibuprofen for reduction of cytokine production in a cell based study of arthritis, (28), for long term use up to a half teaspoon/2500-3000 mg of ginger would be safe from excessive blood thinning effects, more than that consistently may increase risk of easy bruising or bleeding as it also contains phytocoumarins, (29); anandamide (one of our endogenous cannabinoids, which is chemically similar to the euphoria causing cannabinoid THC found in marijuana; cardamonin found in the spice cardamom; the herb Artemisia vestita – Russian Wormwood; Falcarindol found in carrots; Furonaphthoquinone found in the fruit Crataegus pinnatifida (Chinese Hawthorn); garcinone B, found in green fruit hulls of Garcinia mangostana, (18); Glossogyne tenuifolia extract, an herbal supplement used in traditional Chinese medicine sold as Devil’s Claw Extract in English language herbal supplement; Guggulsterone an extract of the resin, called gugal, of the Mukul myrrh tree which is commonly used in ayurveda traditional health care; Honokiol is an extract from Magnolia bark, seeds and leaves traditionally used in eastern/Asian medicine within herbal teas, (19); Hypoestoxide is used in Nigerian medicine and is isolated from the Hypoestes rosea, a plant native to Africa, (20); Isorhapontigenin an analog of resveratrol found in the Chinese herb Gnetum cleistostachyum; Cortex cinnamomi found in the spice cinnamon, an extract from the bark of the Chinese cassia an evergreen tree used in Korean medicine, (21); cryptotanshinone found in the roots of the Salvia miltiorrhiza Bunge (Danshen) plant used in Chinese medicine, (22); Black Rice Extract used in traditional Eastern medicine; Danshensu, found in Salvia miltiorrhiza, (23); diterpenoids are a group of phytonutrients found in many herbs including rosemary, sage and the medicinal herb Gingko biloba, (24, see Table 11.7, visible in this link , lower left corner, 25); Ent-kaurane diterpenoids isolated from a few plants including the fruit of the coffee bean plant, (30); Evodiamine, an extract from the Chinese herbal medicinal plant Evodia rutaecarpa (31); Fomes fomentarius extract of the fungus known as Tinder Conk mushroom or Hoof Fungus; Fucoidan, a polysaccahride found in many species of brown algae and seaweeds; Gallic acid found in tea leaves, red wine and some red plants such as pomegranate, sumac, red raspberries, strawberries, blackberries, red radish, onions, and other plants, used in Ayurveda traditional health care (see 5.2 Phenolic Acids, 32); Ganoderma lucidum, the Lingzhi mushroom used in traditional Chinese medicine; Garcinol, found in the Garcinia indica plant used traditionally in its native tropical growing region to make a sweet drink from the fruit known as Kokum in India and Mangosteen in English, (33); Ginkgolide B, found in the Chinese medicinal tree Gingko biloba, (34); Glycyrrhizin, a sweet flavored extract of Glycyrrhiza glabra (licorice) root, (35); Halofuginone, derived synthetically from fegrifugine or from quinazolinone alkaloid from the Chinese herb Dichroa febrifuga (Chang Shan) hydrangea in English (36); Hematein, found in logwood,Used as a chemical stain & indicator of metals, changing to different colors in the presence of different metals. (37); Herbal compound 861, an extract from ten herbs used in traditional Chinese medicine, (38); Hydoxyethyl starch, branched amylopectin, Used in intravenous infusions (6%) as a plasma volume expander, may cause increased bleeding risk and long term renal damage, especially in critically ill patients. (39); Hydroxyethylpuerarin, (HEP), extract from the dried root of Puerariae radix, an herb used in Chinese traditional medicine (40); mulberry anthocyanins; . There are 700, not all naturally derived, I will be adding a few more from the list.
    (11)
  • cloricromene, a coumarin derivative (medication used in Western medicine) (11) .

Disclaimer: This information is being provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individualized health care guidance. Please see an individual health care provider for individual health care services.

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