Translational medicine – getting research to the patient.

We fundraise for research for cures to disease yet sadly it seems too long for patients living uncomfortably in the present. Seventeen years was an average found in one research study about how long it takes for medical research results to make it into the doctor office and to the patient. Much of the information about magnesium in the last post dates back as far as the 1960s and 70s, that is almost 60 years, not 17. Some discoveries were made by Mildred Seelig, a primary researcher in the role of magnesium in health , and coauthor of one of the books in the reference list (The Magnesium Factor, 38).

Health care choices and food policy regulations affect all age groups. Medicating symptoms instead of treating underlying nutrient deficiency or imbalance can be costly, ineffective, and possibly be allowing chronic degeneration to be occuring due to lack of the nutrient. Nutrient deficiency or imbalance might be due to dietary lack, metabolic differences, malabsorption, or increased needs due to illness or some other reason. Adults and children have been experiencing chronic illness at increased rates in the Unites States and other developed and developing nations.

In the U.S. 43% of children had a chronic health issue (from a list of 20 included in the study) – 32 million children. The number increases to 54.1% when “overweight, obesity, or being at risk for developmental delays are included.” The chronic conditions cause special health care needs for 19.2%, 14.2 million of the chilren. (ref)

While sadly Mildred Seelig passed away before she could see her work reach the majority of patients, young and old, her coauthor for The Magnesium Factor, Andrea Rosanoff, PhD , is still alive and working on the use of magnesium topically for healthcare purposes. Hopefully her work will reach the doctor’s office and the patient before another 17, or 60 years have passed.

Not only are many medications prescribed for symptoms of magnesium deficiency instead of educating on magnesium sources, there are many medications that may decrease magnesium levels. See “Drug Interctions” for individual details, the list includes positive or negative effects – increasing or decreasing efficiency of supplements of Magnesium glycinate -as a prescribed ‘drug’ ( drugbank.ca/drugs/Magnesiuum glycinate). Many of the anti-cholinergics mentioned in Table 1, (ref), are also on the list of drugs that cause drug interactions with magnesium glycinate – decreasing its effectiveness. Anti-cholinergics have been associated with increased risk of dementia, especially with greater use, or multiple use, (ref) , and with increased risk fr recurrent falls in postmenopausal women. (ref)

Anti-cholinergics may include drugs prescribed as:

  • antidepressants, (Amitriptyline),*
  • antipsychotics, (Olanzapine),*
  • for asthma, (antihistamine- Diphenhydramine),*
  • urinary bladder problems, (urinary antimuscarinic –Flavoxate),*
  • muscle spasms, (skeletal muscle relaxant – Orphenadrine),*
  • and other issues.
  • *Anticholinergic Medications from Table 1 (ref) that are also on the drug interaction list as drugs that may decrease the therapeutic efficacy of Magnesium glycinate if prescribed as a supplement/drug. (drugbank.ca/drugs/Magnesiuum glycinate)

Olanzapine also has a significant risk of causing Type 2 Diabetes and/or excessive weight gain with extended use and withdrawal symptoms may include severe increased anxiety and suicidal or homocidal urges. Type 2 Diabetes and anxiety can be symptoms of chronic magnesium deficiency.

Health is worth the effort – pain is a symptom of a problem and a signal to figure out what to change to stop the pain – by improving the underlying problem. Sometimes change is age related and adjustments might need to include recognizing that metabolism has slowed, less calories is needed but protein becomes more important, and, recovery from illness, injury, or extended effort might take longer – so be more cautious about risk. Sometimes change is needed in the standard of care – to include preventative screening and education when health symptoms are still in early stages, before chronic degeneration or cancerous changes occur.

Translational medicine – 60 years is too long to wait for life-saving information to reach patients, 17 years is too long too.

Sadly it can even take more than a hundred years for research findings to benefit the consumer. The use of aluminum as an anti-caking agent in baking powder is still common in the U.S. food supply and it was strongly recommended to be removed from foods as an anti-caking agent or food preservative as long ago as 1911. (Gies, 1911, page 44, Ch.4, ref)

The U.S. consumer who includes processed convenience foods in their diet may be getting 100 milligrams of aluminum per day or more, with an average estimate between 2 and 25 milligrams. The provisional tolerable weekly intake for aluminum was lowered by the FAO/WHO Expert Committee in 2006 from 7 milligrams per kilogram of body weight (~490 mg/wk for a 70 kg/154 lb person) to 1 milligram per kilogram of body weight. The change was due to findings showing a potential risk to reproductive and nervous system development at lower doses than previously thought. (page 45, Ch.4, ref)

I love delicious and/or convenient food, however I love health more. I also like economical, effective healthcare solutions for myself, my family, and everyone else – because it is also better for the planet. When we use toxins in our food supply or food production those toxins are also getting into the environment and wildlife’s food and water supply. Teamwork – we humans are part of the food chain, not just at the top of it.

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.

Magnesium – essential for eighty percent of our body’s chemistry.

Magnesium is a trace mineral essential for 80% of body function, (muscular contractions, energy production, removal of infected or precancerous cells, etc). It is used in over 300 enzymes required for metabolism and other chemical reactions in the body such as synthesis of DNA or proteins. (1)

This post is eleven pages long and can be read as a tabbed document: (doc)

Health Conditions linked to Magnesium inadequacy.

  • Circulatory System: Hypertension, Heart Disease, Stroke, Arrhythmias, Atrial fibrillation, Dyslipedemias.
  • Metabolic: Diabetes, Metabolic Syndrome.
  • Respiratory: Asthma, COPD, Other Lung/Respiratory.
  • Central Nervous System (CNS): Depression, Anxiety, ADHD, Migraine, Pain Relief, Addiction, Sleeplessness, Stress.
  • Muscle/Skeletal: Low Back Pain, Osteoarthritis, Other musculoskeletal (~ muscle cramps, twitches, other chronic joint pain), Osteoporosis, Sarcopenia.
  • Immune System/Other: Pre-eclampsia, Kidney disease, Crohn’s Disease, Chronic Fatigue Syndrome, Colon inflammatory diseases/IBD, Inflammation, Some Cancers.
  • (todaysdietitian/Modern Day Human Magnesium Requirements)(Seelig/Rosanoff, 2003)

Calcium/Magnesium ratio within cells affects our health.

When magnesium within cells is lower than normal calcium is allowed to enter in excess. Elevated amounts of calcium within the interior of cells acts as a signal to start different types of activity. Increased calcium to magnesium balance within a cell may cause different actions based on the type of cell.

  • Elevated calcium to magnesium ratio within cells could cause blood vessels to constrict which would increase blood pressure. Vasoconstriction within the heart could cause a random heart rate (arrthymias). Platelets within the blood would become stickier and more prone to clot which could increase risk of strokes.
  • Cholesterol and glucose over-production may occur in liver cells. Glucose uptake by muscle and fat cells could decrease. Insulin over-production could occur in pancreas cells. Which could lead to Type 2 Diabetes or Metabolic Syndrome.
  • (39, 40, 41, 42) (todaysdietitian/Modern Day Human Mg Requirements)

Summary Points:

  • Magnesium is essential for 80% of body function, (muscular contractions, energy production, removal of infected or precancerous cells, etc), (1),
  • Adequate protein and phospholipids (ATP-AdenosineTriPhosphate –> energy release –> ADP-AdenosineDiPhosphate) are needed for cells to be able to have a full reserve supply of magnesium. (MgATP, 6, 7, 8) Magnesium is located within cells primarily (greater than 99%, 12), as free ion or in an inactive form on molecules of protein or ATP., which means typical blood based lab tests are not helpful for diagnosing chronically low levels of magnesium. See a previous post for more information, food sources and supplement types, and a free etext reference.
  • Magnesium adequacy through diet or supplementation may help improve symptoms for patients with migraine headaches, Alzheimer’s dementia, hypertension, cardiovascular disease, recovery after a cerebrovascular stroke, and type 2 diabetes mellitus (type 2 DM). (9) Muscle cramps may be due to low magnesium levels (9) or an imbalance with calcium levels.
  • Magnesium supplementation may also help some types of psychiatric conditions such as anxiety, depression, bipolar disorder, schizophrenia. See: Magnesium and the Brain: The original chill pill, (psychologytoday.com). Mental health problems have been escalating in the U.S. and other developed countries, lack of jobs and increased social isolation and cyberbullying are involved, however magnesium/calcium imbalance are also factors. See: Latest Suicide Data Show the Depth of U.S. Mental Health Crisis, (bloomberg.com).
  • While you need adequate intake of protein for holding reserve supplies of magnesium within cells, you need adequate magnesium for the body to be able to build new proteins or modify protein structure, and to build more DNA or RNA (which uses the nucleotide ATP), (9, 10, 11, 12, 13, 14, 15) and in ATP hydrolysis (release of the stored energy from glucose metabolism in the Kreb’s cycle), (18) and the Kreb’s cycle. (7) Magnesium deficiency led to lower levels of ATP within red blood cells and increased amounts of ADP, from a 6:1 ratio of ATP:ADP to 2.5:1 at the lowest magnesium level. (19)
  • Which means supplementing only magnesium or only protein may not fully help protect against cardiovascular stroke or migraine pain or other symptoms associated with magnesium deficiency such as hypertension and Type 2 Diabetes.
  • Cancer prevention may also be possible by preventing chronic low levels of magnesium as mutations in DNA may be more likely with inadequate magnesium. Excess calcium or imbalance in vitamin D and calcium/magnesium balance may also be involved in increased cancer risk. (10, 13) Magnesium is used by white blood cells during apoptosis of infected or damaged cells and autophagy, the removal of cells by white blood cells, may help protect against Alzheimer’s dementia. Both apoptosis and autophagy are the typical defense against precancerous cells or mismarked cells that may lead to autoimmune reactions. Once cancer is established magnesium supplements would be inadequate alone as a treatment and would also be providing the nutrient to the cancer cells.

Magnesium and calcium are electrolytes – electrically active ions similar to sodium and potassium.

Magnesium is an electrically active trace mineral/metal that is predominantly found within cell fluid and bone matrix. Only about one percent of the body’s magnesium is found in the blood plasma fluid, circulating throughout the body within blood vessels, and also through the lymphatic and glymphatic systems. (Gervin 1983, ref) (interstitial fluid) Calcium is chemically electrically active in a similar way to magnesium. Both metals can donate or accept two protons and are chemically written with a +2, while sodium and potassium can donate or accept one proton which would be written as +1.

Sodium and potassium are typically referred to as electrolytes however calcium, magnesium and other electrically active ions are also found in blood plasma and in the fluid around cells, called extracellular fluid or interstitial fluid. The fluid within cells is called intracellular fluid or cytoplasm and it also contains ions/electrolytes. The balance of ions within the different types of fluid varies somewhat however the overall average is similar to the balance of ions in sea water. The total fluid volume is about 60% of our body’s weight, of that most is found within cells, 60% intracellular fluid, and of the 40% extracellular fluid, 20% is blood plasma transported in arteries and veins, and 80% is interstitial fluid, transported in the lymphatic system. (Lymphatic fluid, 4) Magnesium would be in greater concentration in the 60% intracellular fluid and calcium would be in greater concentration in the 40% extracellular fluid.

Magnesium powers membrane transport channels – a natural calcium channel blocker.

Within the cells magnesium may be used within enzymes, over 300 require the trace mineral, or may provide their electrical power to cell membrane transport channels which allow certain chemicals to enter the cell while blocking others – when adequate magnesium ions are available to block the channels including some involved in sodium/potassium balance. (16, 18) Magnesium deficiency seemed to decrease the activity of the sodium/potassium channels in an animal based study. It led to increased intracellular sodium levels which could be a mechanism for the increased risk of arrythmias (irregular heart rate) with magnesium deficiency. (17)

Magnesium in muscles and the inner ear (tinnitus).

Magnesium causes relaxation of muscles – blocking entry of calcium into the muscle fiber, and calcium entry causes muscle contractions within smooth muscle fibers (such as the muscle fibers of the gastrointestinal tract) or striated muscle fibers (found in the muscles with voluntary control such as those of the arms and legs, and also in the heart which is not under voluntary control). (31, 32, 33, 34, 35, 36, 37) Magnesium deficiency can be an underlying cause of muscle cramps or twitches (such as a nonstop twitch in the eyelids) (9), and may also be a factor in tinnitus (nonstop or intermittent ringing or buzzing sounds in the ears/ear). (28) Daily supplementation with 532 milligrams of magnesium was found helpful to relieve symptoms of tinnitus in a small clinical trial. (30) Magnesium inhibits glutamate channels which are involved in activating the hair cells of the ear canal. It may also help by helping relax blood vessels to the inner ear and increasing blood flow. (29)

Magnesium is stored within the cell in an inactive form on protein molecules or ATP.

Even within the cells the majority of magnesium stores are not available in the electrically active form. Most of the back-stock of magnesium within cells is stored on proteins or molecules of ATP (the nucleotide involved in the Kreb’s cycle production of usable energy {ATP bonds} from glucose). (MgATP, 6, 7, 8)

This means magnesium deficiency can take a long time to be seen because of the extra stored within cells on proteins and ATP and the extra stored within our bone matrix can be slowly released to continue powering the 300+ enzymes and membrane channels in every cell of the body. What happens eventually however is a depletion of the backstock of magnesium on the cellular proteins and ATP and osteoporosis can develop in the bone matrix leaving fragile bones at risk for fractures — and also cell membranes at risk to an influx of too much calcium, or other excitatory chemicals such as glutamates or aspartic acid/aspartate, leaving brain cells at increased risk from food additives, or dehydration, or ischemic stroke.

Protein deficiency in the diet or increased metabolic need for protein might increase risk of low magnesium levels being available in case of a stroke. If a stroke occurred treating with intravenous magnesium fairly soon can help reduce cell damage and preserve abilities. When the body is well supplied with protein, ATP, and magnesium then the stored magnesium would be available in case of a stroke or physical brain trauma. If protein availability was limited the damage from a stroke might be more severe due to less magnesium being available for release.

Protein-energy malnutrition is a type of malnutrition involving a diet low in protein more than calories. The condition was formerly known as kwashiorkor and was first recognized in tropical infants/children. Severe edema with a bloated abdomen is typical visible symptom. (See image, page 30, 46) When magnesium deficiency is also severe the condition is more likely to result in death and strokes are also more common. The serum magnesium level of children with protein-energy malnutrition was found to be significantly lower than in the control group. Low magnesium in drinking water has been associated with increased risk of cerebrovascular disease or death by stroke. (45)

Incomplete protein in the diet seems to be involved – plant sources of protein do not all contain adequate amounts of all the essential amino acids. Missionary work historically may have increased the risk of Protein-energy malnutrition in recently weaned toddlers due to an educational message that eating insects is wrong – eating a diet with inadequate amounts of essential amino acids is what is wrong. In modern times, unfortunately, children in Africa are now being taught to not catch and eat crickets because they are likely contaminated with the pesticides that are commonly used on farm fields.

The amino acids considered essential for a child’s diet include: Arginine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, Valine. The traditional African diet in some areas includes complete protein from peanuts and cowpeas are only low in tryptophan. (46) Millet and sorghum are commonly used grains which are low in tryptophan, lysine, methionine, and threonine. (47) The nutrient content of food insects depends on their stage of growth, however on average they are considered a good source of complete protein – providing a similar ratio of essential amino acids as meat or fish. Food insects are also a good source of essential fatty acids, similar to fish, and provide fiber and trace minerals including “copper, iron, magnesium, manganese, phosphorous, selenium and zinc.” (48)

Food insects and breastmilk also have in common N-acetyl glucosamine (within insects it is found in the form of the fiber chitin which is not typically thought of as digestible by humans however the enzyme chitinase has been found in human gastric fluid). (49, p 74, section 6.1.8: 50) Intake of N-acetyl glucosamine may help support a healthy intestinal mucousal lining. Impaired mucous lining of the intestine and reduced amounts of “enterocyte heparan sulfate proteoglycan (HSPG),” and “abnormal sulfated glycosaminoglycan (GAG) metabolism” have been observed in patients with protein-energy malnutrition (kwashiorkor). (49) Providing magnesium sulfate by intramuscular injection helped survival for children with protein-energy malnutrition compared to the control group in a small clinical trial. (51)

Magnesium is needed for vitamin D, CoQ10, and cholesterol production.

Magnesium deficiency can lead to low levels of the inactive and active form of vitamin D. Magnesium supplementation is needed to reverse a type of bone degenerative condition called vitamin D resistant rickets. (20) Supplementing with vitamin D and/or calcium has been popular however the benefits against fracture risk and osteoporosis have been unclear or show little benefit. (22) The need for magnesium supplementation instead of or in addition to vitamin D and calcium supplements is in area worth further study. (21) Magnesium is also involved in earlier steps involved in vitamin D production – biosynthesis of cholesterol (23) from which vitamin D can be formed in the skin when sunshine is available.

Magnesium acts similarly to statin medications and is the natural version of a calcium channel blocker medication. (23) Statins have been prescribed to many people in hopes that chemically inhibiting the production of cholesterol would help protect against heart disease, unfortunately the theory has not been proven effective – while cholesterol levels are reduced in about half the patients using the medication, the lower cholesterol levels have not also been associated with reduced mortality from cardiovasclar risks. For patients without heart failure or renal dialysis or for those over age 75 the use of statin medications helped prevent revascularization and major coronary events in about 20% of research trials that were reviewed. (24)

The cardiovascular benefits of statin medications may be due to the inhibition of an interim step in cholesterol formation – mevalonate. Magnesium would also affect mevalonate formation however in a regulatory way – controlling whether or not the reaction happens rather than only inhibiting it. (23) β-Hydroxy β-methylglutaryl-CoA, (HMG Co A) is converted into mevalonate which then can be converted into cholesterol or the provitamin coenzyme Q10. (26)

Lack of CoQ10 may cause muscle pain and lead to mitochondrial dysfunction.

Statin medication use may cause muscle and joint pain in some users, possibly due to inhibition of Coenzyme Q10 production. Supplements of CoQ10 (200mg/day) may help reduce the muscle pain symptoms for some patients and could also be protecting against a risk of mitochondrial dysfunction caused by low levels of the the coenzyme. (25)

  • Mitochondrial dysfunction may be a cause of chronic fatigue – low energy production by mitochondria within cells would leave every function in the body with less energy to perform their jobs. Mitochondrial dysfunction may be involved in many conditions including autism, Alzheimer’s disease, muscular dystrophy, Lou Gehrig’s disease, diabetes and cancer. (clevelandclinic/mitochondrial diseases)

Magnesium helps protect health, and improve our energy level and mood.

Symptoms of magnesium deficiency are often treated with medications (such as calcium channel blockers or statins) instead of providing magnesium. Other medications commonly used to treat symptoms that might involve magnesium deficiency include: beta blockers, blood thinners, anti-hypertensive medications, insulin or metformin, anti-depressants, anti-anxiety medications, anti-inflammatory medications. (43) (todaysdietitian/Modern Day Human Magnesium Requirements)

Adequate protein and phospholipids are also needed for cells to be able to store extra magnesium in an electrically inactive form and magnesium is needed for their synthesis. This might help explain why supplements of magnesium help some patients more than others. Someone who is more chronically ill or malnourished or who has impaired metabolism may need more complete nutrition support rather than only providing a magnesium supplement. Topical supplements of magnesium may be needed for patients with malabsorption problems or for those who don’t seem to be helped by increasing dietary sources.

Excess calcium in proportion to magnesium in the diet or from supplements may also be part of the problem for some patients. (44) The average modern diet can include calcium rich dairy products at each meal and snack. Tofu, beans, almonds, sesame seeds, and dark leafy green vegetables are also good sources of calcium.

Free Continuing Education credit for nutritionists/diet techs:

  • For any dietitians or diet techs, much of the first reference list is from a free continuing education webinar, register for this: Andrea Rosanoff, PhD, and Stella Lucia Volpe, PhD, RDN, ACSM-CEP, FACSM, Recorded Webinar: Modern Day Human Magnesium Requirements: The RDN’s Role, Today’s Dietitian https://ce.todaysdietitian.com/node/69241#group-tabs-node-course-default1  The second list is from the last post from the section about magnesium and hypercoaguability.

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.

References

  1. Workinger JL, Doyle RP, Bortz J. Challenges in the diagnosis of magnesium status. Nutrients. 2018;10(9):1202. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163803/
  2. Gervin CA, Nichols WM, Chvapil M, Wangensteen SL. Zinc transport by the heart lymphatic system after acute myocardial infarction., J Surg Res. 1983 Oct;35(4):340-50. https://www.ncbi.nlm.nih.gov/pubmed/6621029
  3. Niels Fogh-Andersen, Burton M. Altura, Bella T. Altura, and Ole Siggaard-Andersen, Composition of Interstitial Fluid, Clin. Chem. 41/10, 1522-1525 (1995) https://pdfs.semanticscholar.org/6955/f9bc101b8adff35b700906dcf77d683367f0.pdf
  4. Lymphatic Fluid and Immunotherapy, maxwellbioscinces.com, https://maxwellbiosciences.com/articles/uncategorized/lymphatic-fluid-immunotherapy
  5. Differences between blood and lymph, vedantu.com, https://www.vedantu.com/biology/difference-between-blood-and-lymph
  6. Storer AC, Cornish-Bowden A. Concentration of MgATP2- and other ions in solution. Calculation of the true concentrations of species present in mixtures of associating ions. Biochem J. 1976;159(1):1-5. https://pdfs.semanticscholar.org/a85b/95b80f2c0fd41f8a39a7c7768887ee784522.pdf
  7. Garfinkel L, Garfinkel D. Magnesium regulation of the glycolytic pathway and the enzymes involved. Magnesium. 1985;4(2-3):60-72. https://www.ncbi.nlm.nih.gov/pubmed/2931560
  8. Wilson JE, Chin A. Chelation of divalent cations by ATP, studied by titration calorimetry. Analytical Biochem. 1991;193(1):16-19. https://www.ncbi.nlm.nih.gov/pubmed/1645933
  9. Volpe SL. Magnesium in disease prevention and overall health. Adv Nutr. 2013;4(3):378S383S. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650510/
  10. Abdelgawad IA, El-Mously RH, Saber MM, Mansour OA, Shouman SA. Significance of serum levels of vitamin D and some related minerals in breast cancer patients. Int J Clin Exp Pathol. 2015;8(4):4074-4082. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466982/
  11. Romani AM. Magnesium in health and disease. Met Ions Life Sci. 2013;13:49-79. https://www.ncbi.nlm.nih.gov/pubmed/24470089
  12. Long S, Romani AM. Role of cellular magnesium in human diseases. Austin J Nutr Food Sci. 2014;2(10):1051. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379450/
  13. Rubin H. Central roles of Mg2+ and MgATP2- in the regulation of protein synthesis and cell proliferation: significance for neoplastic transformation. Adv Cancer Res. 2005;93:1-58. https://www.ncbi.nlm.nih.gov/pubmed/15797443
  14. George GA, Heaton FW. Effect of magnesium deficiency on energy metabolism and protein synthesis by liver. Int J Biochem. 1978;9(6):421-425. https://www.sciencedirect.com/science/article/pii/0020711X78900551
  15. Weisinger JR, Bellorin-Font E. Magnesium and phosphorus. Lancet. 1998;352(9125):391-396. https://www.thelancet.com/journals/lancet/article/PIIS0140673697105359/fulltext
  16. Dorup I, Skajaa K, Thybo NK. Oral magnesium supplementation restores the concentrations of magnesium, potassium and sodium-potassium pumps in skeletal muscle of patients receiving diuretic treatment. J Intern Med. 1993;233(2):117-123. https://www.ncbi.nlm.nih.gov/pubmed/8381850
  17. Fischer PW, Giroux A. Effects of dietary magnesium on sodium-potassium pump action in the heart of rats. J Nutr. 1987;117(12):2091-2095. https://www.ncbi.nlm.nih.gov/pubmed/2826728
  18. Fagher B, Sjögren A, Monti M. A microcalorimetric study of the sodium-potassium-pump and thermogenesis in human skeletal muscle. Acta Physiol Scand. 1987;131(3):355-360. https://www.ncbi.nlm.nih.gov/pubmed/2447746
  19. Flatman PW, Lew VL. The magnesium dependence of sodium-pump-mediated sodiumpotassium and sodium-sodium exchange in intact human red cells. J Physiol. 1981;315:421-446. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1249391/
  20. Deng X, Song Y, Manson JE, et al. Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III. BMC Med. 2013;11:187. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765911/
  21. Rosanoff A, Dai Q, Shapses SA. Essential nutrient interactions: does low or suboptimal magnesium status interact with vitamin D and/or calcium status? Adv Nutr. 2016;7(1):25-43. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4717874/
  22. Jill Jin, MD, MPH, Vitamin D and Calcium for Preventing Fractures, Guidelines, JAMA Patient Page, JAMA Network, April 17, 2018 https://jamanetwork.com/journals/jama/fullarticle/2678617
  23. Rosanoff A, Seelig MS. Comparison of mechanism and functional effects of magnesium and statin pharmaceuticals. J Am Coll Nutr. 2004;23(5):501S-505S. https://www.ncbi.nlm.nih.gov/pubmed/15466951
  24. Cholesterol Treatment Trialists’ Collaboration  Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials., The Lancet, Vol 393, Issue 10170, pp407-415, Feb. 02, 2019, https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31942-1/fulltext
  25. Deichmann R, Lavie C, Andrews S. Coenzyme q10 and statin-induced mitochondrial dysfunction. Ochsner J. 2010;10(1):16–21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096178/
  26. Pacanowski MA, Frye RF, Enogieru O, Schofield RS, Zineh I. Plasma Coenzyme Q10 Predicts Lipid-lowering Response to High-Dose Atorvastatin. J Clin Lipidol. 2008;2(4):289–297. doi:10.1016/j.jacl.2008.05.001 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2598393/
  27. Mitochondrial Diseases, ClevelandClinic.org, https://my.clevelandclinic.org/health/diseases/15612-mitochondrial-diseases
  28. Tinnitus and Magnesium, tinnitus.org, https://www.tinnitus.org.uk/tinnitus-and-magnesium
  29. Joseph Mercola, MD, Can Magnesium Relieve Your Tinnitus?, Prohealth.com, https://www.prohealth.com/library/can-magnesium-relieve-your-tinnitus-47779
  30. Cevette MJ, Barrs DM, Patel A, et al., Phase 2 study examining magnesium-dependent tinnitus., Int Tinnitus J. 2011;16(2):168-73. https://www.ncbi.nlm.nih.gov/pubmed/22249877
  31. Zhang A, Carella A, Altura BT, Altura BM. Interactions of magnesium and chloride ions on tone and contractility of vascular muscle. Eur J Pharmacol. 1991;203(2):223-235. https://www.ncbi.nlm.nih.gov/pubmed/1800119
  32. Altura BM, Altura BT. Role of magnesium ions in contractility of blood vessels and skeletal muscles. Magnesium Bull. 1981;3(1a):102-114. http://www.magnesium-ges.de/jdownloads/Literatur/Altura/altura_1981_role_of_magnesium_ions_in_contractility_of_blood_vessels_and_skeletal_muscles_444.pdf
  33. Konishi M. Cytoplasmic free concentrations of Ca2+ and Mg2+ in skeletal muscle fibers at rest and during contraction. Jpn J Physiol. 1998;48(6):421-438. https://www.ncbi.nlm.nih.gov/pubmed/10021496
  34. Yang Z, Wang J, Altura BT, Altura BM. Extracellular magnesium deficiency induces contraction of arterial muscle: role of PI3-kinases and MAPK signaling pathways. Pflugers Arch. 2000;439(3):240-247. https://www.ncbi.nlm.nih.gov/pubmed/10650973
  35. Yang ZW, Gebrewold A, Nowakowski M, Altura BT, Altura BM. Mg(2+)-induced endothelium-dependent relaxation of blood vessels and blood pressure lowering: role of NO. Am J Physiol Regul Integr Comp Physiol. 2000;278(3):R628-R639. https://www.physiology.org/doi/full/10.1152/ajpregu.2000.278.3.R628
  36. Yang ZW, Wang J, Zheng T, Altura BT, Altura BM. Low Mg(2+) induces contraction and Ca(2+) rises in cerebral arteries: roles of ca(2+), PKC, and PI3. Am J Physiol Heart Circ Physiol. 2000;279(6):H2898-H2907. https://www.physiology.org/doi/pdf/10.1152/ajpheart.2000.279.6.H2898
  37. Turlapaty PD, Altura BM. Magnesium deficiency produces spasms of coronary arteries: relationship to etiology of sudden death ischemic heart disease. Science. 1980;208(4440):198-200. https://www.ncbi.nlm.nih.gov/pubmed/7361117
  38. Seelig MS, Rosanoff A. The Magnesium Factor. 1st ed. New York, NY: Avery Penguin Group; 2003:278-279; 369-370 https://www.barnesandnoble.com/p/the-magnesium-factor-mildred-seelig/
  39. Resnick L. The cellular ionic basis of hypertension and allied clinical conditions. Prog Cardiovasc Dis. 1999;42(1):1-22. https://www.ncbi.nlm.nih.gov/pubmed/10505490
  40. Resnick LM. Ionic basis of hypertension, insulin resistance, vascular disease, and related disorders. The mechanism of “syndrome X.” Am J Hypertens. 1993;6(4):123S-134S. https://www.ncbi.nlm.nih.gov/pubmed/8507440
  41. Rosanoff A. Nutritional magnesium is associated with metabolic syndrome, cardiovascular disease and its risk factors, and other NCDs: a bibliography. Magnesium Education website. http://www.magnesiumeducation.com/the-mg-hypothesis-of-cardiovascular-disease-abibliography
  42. Rosanoff A, Weaver CM, Rude RK. Suboptimal magnesium status in the United States: are the health consequences underestimated? Nutr Rev. 2012;70(3):153-164. https://www.mgwater.com/articles/Rosanoff/(09)%20Suboptimal%20Magnesium%20Status%20in%20the%20United%20States.pdf
  43. Rosanoff A, Capron E, Barak P, Mathews B, Nielsen FH. Edible plant tissue and soil calcium:magnesium ratios: data too sparse to assess implications for human health. Crop Pasture Sci. 2015;66:1265-1277. http://agris.fao.org/agris-search/search.do?recordID=US201600101821
  44. Rosanoff A. Rising Ca:Mg intake ratio from food in USA Adults: a concern? Magnesium Res. 2010;23(4):S181-S193. https://www.mgwater.com/Ca-Mg.pdf
  45. Karakelleoglu C, Orbak Z, Ozturk F, Kosan C. Hypomagnesaemia as a mortality risk factor in protein-energy malnutrition. J Health Popul Nutr. 2011;29(2):181–182. doi:10.3329/jhpn.v29i2.7863 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126992/
  46. Florence Dunkel, Learning from Sanambele: Role of Food Insects in Village Nutritional Health, Montana State University-Bozeman (a Power Point presentation) http://www.montana.edu/mali/documents/pptsaspdfs/worldHungerDunkelSanambelepresentationsmallpdfvsn.pdf
  47. Sorghum and Millets in Human Nature, fao.org, http://www.fao.org/3/T0818E/T0818E0d.htm
  48. The Contribution of Insects to Food Security, Livelihoods and the Environment, fao.org, http://www.fao.org/3/i3264e/i3264e00.pdf
  49. Beatrice Amadi, Andrew O Fagbemi, Paul Kelly, et al., Reduced production of sulfated glycosaminoglycans occurs in Zambian children with kwashiorkor but not marasmus., The American Journal of Clinical Nutrition, Vol 89, Issue 2, Feb 2009, pp 592–600 https://academic.oup.com/ajcn/article/89/2/592/4596718
  50. Arnold van Huis, Joost Van Itterbeeck, Harmke Klunder, et al., Edible insects: Future prospects for food and feed security, Food and Agriculture Organization of the United Nations, Rome, 2013, FAO.org, http://edepot.wur.nl/258042
  51. Joan L.Caddell, MD., Magnesium in the therapy of protein-caloriemalnutrition of childhood., The Journal of Pediatrics, Vol 66, Issue 2, Feb 1965, pp 392-413, https://www.sciencedirect.com/science/article/abs/pii/S0022347665801974

Article in the lower right hand column of the Science Direct topic page on Albumin Antibody: – it has a thorough description and graphic (Figure 1) about the blood brain barrier and seizures.

  1. N. Marchi, … D. Janigro, in Encyclopedia of Basic Epilepsy Research, 2009, Inflammation: Cerebrovascular Diseases, Seizures, and Epilepsy Seizures; Epilepsy, and the Blood–Brain Barrier, “Systemic pathologies causing BBB failure may be due to hypertension, stroke, blood hyperosmolarity, or systemically mediated inflammatory processes (due to the production of TNF-α, IL-1β, IL-6, histamine, arachidonic acid, or reactive oxygen species)”

References from the last post on hypercoaguability and the NF-kB inflammatory pathway.

  1. DiNicolantonio JJ, Liu J, O’Keefe JH. Magnesium for the prevention and treatment of cardiovascular disease. Open Heart. 2018;5(2):e000775. Published 2018 Jul 1. doi:10.1136/openhrt-2018-000775 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045762/
  2. Andrea Rosanoff, PhD, and Stella Lucia Volpe, PhD, RDN, ACSM-CEP, FACSM, Recorded Webinar: Modern Day Human Magnesium Requirements: The RDN’s Role, Today’s Dietitian, https://ce.todaysdietitian.com/node/69241#group-tabs-node-course-default1
  3. Karen Skene, Sarah K. Walsh, Oronne Okafor, Nadine Godsman, et al., Acute dietary zinc deficiency in rats exacerbates myocardial ischaemia–reperfusion injury through depletion of glutathione., British Journal of Nutrition, Vol 121, Issue 9 14 May 2019 , pp. 961-973, https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/acute-dietary-zinc-deficiency-in-rats-exacerbates-myocardial-ischaemiareperfusion-injury-through-depletion-of-glutathione/15953E00DA3E69629F36F9F6FE5079A8
  4. Karl T. Weber,1,* William B. Weglicki,2 and Robert U. Simpson3 Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium, Cardiovasc Res. 2009 Feb 15; 81(3): 500–508. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2639130/
  5. Li YC. Vitamin D: roles in renal and cardiovascular protection. Curr Opin Nephrol Hypertens. 2012;21(1):72–79. doi:10.1097/MNH.0b013e32834de4ee https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574163/
  6. Benjamin Senst; Prasanna Tadi; Hajira Basit; Arif Jan., Hypercoaguability, STATPearls, Last Update: April 29, 2019. https://www.ncbi.nlm.nih.gov/books/NBK538251/
  7. Kennedy DO. B Vitamins and the Brain: Mechanisms, Dose and Efficacy–A Review. Nutrients. 2016;8(2):68. Published 2016 Jan 28. doi:10.3390/nu8020068 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772032/

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.

References

  1. Goljan-Geremek A, Geremek M, Puscinska E, Sliwinski P., Venous thromboembolism and sarcoidosis: co-incidence or coexistence?. Cent Eur J Immunol. 2015;40(4):477–480. doi:10.5114/ceji.2015.56972
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737745/
  2. Tarique Hussain, Bie Tan, Gang Li, et al., Modulatory Mechanism of Polyphenols and Nrf2 Signaling, Pathway in LPS Challenged Pregnancy Disorders, Hindawi, Oxidative Medicine and Cellular Longevity, Vol 2017, Article ID 8254289 https://pdfs.semanticscholar.org/7c94/3d7267998a159ed91162e7feea0092d3fffa.pdf
  3. D. Callaway, W. Jiang, K. Lingappan, B. Moorthy, Decreased Survival and Increased Oxygen-Mediated Lung Injury in Mice Lacking Nrf2: Protection by Beta-Naphthoflavone, American Journal of Respiratory and Critical Care Medicine 2019;199:A1158 https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2019.199.1_MeetingAbstracts.A1158
  4. Beta-Naphthoflavone, MedKoo Cat#: 540310, medkoo.com,
    https://www.medkoo.com/products/15806
  5. Chan K, Kan YW. Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci U S A. 1999;96(22):12731–12736. doi:10.1073/pnas.96.22.12731,
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC23072/
  6. Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci. 2016;5:e47. Published 2016 Dec 29. doi:10.1017/jns.2016.41,
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465813/
  7. Wardyn JD, Ponsford AH, Sanderson CM. Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways. Biochem Soc Trans. 2015;43(4):621–626. doi:10.1042/BST20150014
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613495/
  8. Jeon KI, Xu X, Aizawa T, et al. Vinpocetine inhibits NF-kappaB-dependent inflammation via an IKK-dependent but PDE-independent mechanism. Proc Natl Acad Sci U S A. 2010;107(21):9795–9800. doi:10.1073/pnas.0914414107
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906898/
  9. Rachael Rettner, Dietary Supplement Ingredient Linked to Miscarriages, FDA Warns, livescience.com, June 4, 2019,
    https://www.livescience.com/65629-vinpocetine-supplements-miscarriages.html
  10. Hariri BM, McMahon DB, Chen B, et al. Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor. J Biol Chem. 2017;292(20):8484–8497. doi:10.1074/jbc.M116.771949
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437252/
  11. Gupta SC, Sundaram C, Reuter S, Aggarwal BB. Inhibiting NF-κB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta. 2010;1799(10-12):775–787. doi:10.1016/j.bbagrm.2010.05.004
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955987/
  12. Chenyu Chu, Jia Deng, Yi Man, and Yili Qu, Green Tea Extracts Epigallocatechin-3-gallate for Different Treatments, BioMed Research International, Vol 2017, Article ID 5615647
    https://www.hindawi.com/journals/bmri/2017/5615647/
  13. Higgins, Peter D.R., et al. Increased Risk of Venous Thromboembolic Events With Corticosteroid vs Biologic Therapy for Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology 2015: 13(2): 316-321, http://www.cghjournal.org/article/S1542-3565(14)01045-3/abstract
  14. Colburn S, Childers WK, Chacon A, Swailes A, Ahmed FM, Sahi R. The cost of seeking an edge: Recurrent renal infarction in setting of recreational use of anabolic steroids. Ann Med Surg (Lond). 2017;14:25–28. Published 2017 Jan 12. doi:10.1016/j.amsu.2017.01.015
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247564/
  15. Przybycinski et al., Renal Artery Thrombosis in a Bodybuilder using Anabolic Steroid – Case Report, J Sports Med Doping Stud, 2019, 9:1, DOI: 10.4172/2161-0673.1000215,
    https://www.omicsonline.org/open-access-pdfs/renal-artery-thrombosis-in-a-bodybuilder-using-anabolic-steroid–case-report.pdf
  16. Sarcoidosis & Your Organs, Cleveland Clinic,
    https://my.clevelandclinic.org/health/diseases/11865-sarcoidosis–your-organs
  17. Warning – Your Green Tea Isn’t What You Think It Is, Bottom Line Inc.,
    https://bottomlineinc.com/life/tea/warningyour-green-tea-isnt-what-you-think-it-is
  18. Suksamrarn S, et al., Xanthones from the green fruit hulls of Garcinia mangostana., J. Nat. Prod. 2002655761-763, April 17, 2002 https://doi.org/10.1021/np010566 https://www.ncbi.nlm.nih.gov/pubmed/12027762
  19. Fried LE, Arbiser JL. Honokiol, a multifunctional antiangiogenic and antitumor agent. Antioxid Redox Signal. 2009;11(5):1139–1148. doi:10.1089/ars.2009.2440 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842137/
  20. Emmanuel A.Ojo-Amaize, et al., Hypoestoxide, a Novel Anti-inflammatory Natural Diterpene, Inhibits the Activity of IκB Kinase, Cellular Immunology, Vol 209, Issue 2, 1 May 2001, pp 149-157,
    https://www.sciencedirect.com/science/article/abs/pii/S0008874901917988
  21. Choi HM, Jung Y, Park J, et al. Cinnamomi Cortex (Cinnamomum verum) Suppresses Testosterone-induced Benign Prostatic Hyperplasia by Regulating 5α-reductase. Sci Rep. 2016;6:31906. Published 2016 Aug 23. doi:10.1038/srep31906
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994048/
  22. Chen W, Lu Y, Chen G, Huang S. Molecular evidence of cryptotanshinone for treatment and prevention of human cancer. Anticancer Agents Med Chem. 2013;13(7):979–987. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625674/
  23. Cao Y, Chai JG, Chen YC, et al. Beneficial effects of danshensu, an active component of Salvia miltiorrhiza, on homocysteine metabolism via the trans-sulphuration pathway in rats. Br J Pharmacol. 2009;157(3):482–490. doi:10.1111/j.1476-5381.2009.00179.x https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707994/
  24. A. Ludwiczuk, et al., Chapter 11: Terpenoids, Pharmacognosy: Fundamentals, Applications and Strategies,  2017, pp 233-266,
    https://www.sciencedirect.com/science/article/pii/B9780128021040000111
  25. Terpenoids, Science Direct,
    https://www.sciencedirect.com/topics/neuroscience/diterpenoid
  26. Rayati F, Hajmanouchehri F, Najafi E. Comparison of anti-inflammatory and analgesic effects of Ginger powder and Ibuprofen in postsurgical pain model: A randomized, double-blind, case-control clinical trial. Dent Res J (Isfahan). 2017;14(1):1–7.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356382/
  27. E.M.Bartels, V.N.Folmer, H.Bliddal, et al., Efficacy and safety of ginger in osteoarthritis patients: a meta-analysis of randomized placebo-controlled trials., Osteoarthritis and Cartilage, Vol 23, Issue 1, Jan 2015, pp 13-21, https://www.sciencedirect.com/science/article/pii/S106345841401276X
  28. Ribel-Madsen, Søren; Bartels, Else Marie; Stockmarr, Anders, et al., A SynoviocyteModel for Osteoarthritis and Rheumatoid Arthritis: Response to Ibuprofen, Betamethasone, and Ginger Extract—A Cross-Sectional In Vitro Study., Arthritis, 2012, DOI: 10.1155/2012/505842
    http://orbit.dtu.dk/files/52967554/505842.pdf
  29. Herbal Medicines: Anticoagulation Effects, Open Anesthesia,
    https://www.openanesthesia.org/herbal_medicines_anticoagulation_effects/
  30. Xia Wangab, Xingrong Penga, Jing Lu, et al., Ent-kaurane diterpenoids from the cherries of Coffea arabica., Fitoterapia, Vol 132, Jan 2019, pp 7-11,
    https://www.sciencedirect.com/science/article/pii/S0367326X18307846
  31. Xin Zhou, Fengying Ren, Hong Wei, et al., Combination of berberine and evodiamine inhibits intestinal cholesterol absorption in high fat diet induced hyperlipidemic rats., Lipids in Health and Disease, 2017 16:239,
    https://lipidworld.biomedcentral.com/articles/10.1186/s12944-017-0628-x
  32. Renata Nowak, Marta Olech, Natalia Nowacka, Chapter 97 – Plant Polyphenols as Chemopreventive Agents, 5.2 Phenolic Acids, Polyphenols in Human Health and Disease, Vol 2, 2014, pp 1289-1307, https://www.sciencedirect.com/topics/medicine-and-dentistry/gallic-acid
  33. Padhye S, Ahmad A, Oswal N, Sarkar FH. Emerging role of Garcinol, the antioxidant chalcone from Garcinia indica Choisy and its synthetic analogs. J Hematol Oncol. 2009;2:38. Published 2009 Sep 2. doi:10.1186/1756-8722-2-38
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743703/
  34. Ginkgolide B, Science Direct, https://www.sciencedirect.com/topics/medicine-and-dentistry/ginkgolide-b
  35. Glycyrrhizin, Science Direct,
    https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/glycyrrhizin
  36. Halofuginone, Science Direct,
    https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/halofuginone
  37. Hematein, Sciencemadness Wiki, http://www.sciencemadness.org/smwiki/index.php/Hematein
  38. A promising target of anti-fibrotic therapy: herbal compound 861, EurekaAlert Science News, https://www.eurekalert.org/pub_releases/2008-05/wjog-apt091808.php
  39. Hydroxyethyl Starch, Science Direct, https://www.sciencedirect.com/topics/medicine-and-dentistry/hydroxyethyl-starch
  40. Zi-Ying Wang, Xin-Bing Wei, Lin Chen, et al., Neuroprotective Effects of Hydroxyethylpuerarin against Focal Cerebral Ischemia-Reperfusion in Rats., Chinese Journal of Physiology 50(5): 211-216, 2007 https://www.dropbox.com/s/t486fl5ieu1svjs/201412141532230.pdf?dl=0
  41. DiNicolantonio JJ, Liu J, O’Keefe JH. Magnesium for the prevention and treatment of cardiovascular disease. Open Heart. 2018;5(2):e000775. Published 2018 Jul 1. doi:10.1136/openhrt-2018-000775 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045762/
  42. Andrea Rosanoff, PhD, and Stella Lucia Volpe, PhD, RDN, ACSM-CEP, FACSM, Recorded Webinar: Modern Day Human Magnesium Requirements: The RDN’s Role, Today’s Dietitian, https://ce.todaysdietitian.com/node/69241#group-tabs-node-course-default1
  43. Karen Skene, Sarah K. Walsh, Oronne Okafor, Nadine Godsman, et al., Acute dietary zinc deficiency in rats exacerbates myocardial ischaemia–reperfusion injury through depletion of glutathione., British Journal of Nutrition, Vol 121, Issue 9 14 May 2019 , pp. 961-973, https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/acute-dietary-zinc-deficiency-in-rats-exacerbates-myocardial-ischaemiareperfusion-injury-through-depletion-of-glutathione/15953E00DA3E69629F36F9F6FE5079A8
  44. Karl T. Weber,1,* William B. Weglicki,2 and Robert U. Simpson3 Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium, Cardiovasc Res. 2009 Feb 15; 81(3): 500–508. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2639130/
  45. Li YC. Vitamin D: roles in renal and cardiovascular protection. Curr Opin Nephrol Hypertens. 2012;21(1):72–79. doi:10.1097/MNH.0b013e32834de4ee https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574163/
  46. Benjamin Senst; Prasanna Tadi; Hajira Basit; Arif Jan., Hypercoaguability, STATPearls, Last Update: April 29, 2019. https://www.ncbi.nlm.nih.gov/books/NBK538251/
  47. Kennedy DO. B Vitamins and the Brain: Mechanisms, Dose and Efficacy–A Review. Nutrients. 2016;8(2):68. Published 2016 Jan 28. doi:10.3390/nu8020068 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772032/
  • M Wang, W Liu, and T J Webster, Chapter 16: The Promise of Nano metals: Reducing Infection and Increasing Biocompatibility, Trace Metals and Infectious Diseases, Ed. Jerome O Nriagu and Eric P Skaar, Strungmann Forum Reports, (MIT Press, 2015, Cambridge, MA) https://mitpress.mit.edu/books/trace-metals-and-infectious-diseases
  • M L Ackland, J Bornhorst, F V Dedoussis, et al., Chapter 17: Metals in the Environment as Risk Factors for Infectious Diseases, Trace Metals and Infectious Diseases, Ed. Jerome O Nriagu and Eric P Skaar, Strungmann Forum Reports, (MIT Press, 2015, Cambridge, MA) https://mitpress.mit.edu/books/trace-metals-and-infectious-diseases
  • Wessels, I., H. Haase, G. Engelhardt, L. Rink, and P. Uciechowski, 2013. Zinc Deficiency Induces Production of the Pro-Inflammatory Cytokines IL-1beta and TNF alpha in Promyeloid Cells via Epigenetic and Redox-Dependent Mechanisms. J. Nutr. Biochem. 24:289-297. https://www.ncbi.nlm.nih.gov/pubmed/22902331