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Evidence-Based, Integrative Considerations with Respect to Immune Support & COVID-19

Evidence-Based, Integrative Considerations with Respect to Immune Support & COVID-19

CAVEAT: integrative medicine measures have thus far NOT been validated in any human trials with respect to COVID-19, so in no way, shape, or form is this article specifically recommending any natural medicine treatments for COVID-19.

I had the privilege of attending National University of Natural Medicine to become a naturopathic doctor (ND), and one of my favorite professors is the brilliant Dr. Heather Zwickey, PhD, who taught us immunology and currently serves as executive program chair at NUNM and as the principal investigator at the Helfgott Research Institute. As an infectious diseases expert, she did her post-doctoral research at Yale, and one of her life purposes is to prove the efficacy of natural medicine with regard to the immunological response.

Recently, in one of my ND Facebook groups, a colleague shared Dr. Zwickey’s thoughts regarding COVID-19, with her permission, sent to her via an email exchange. Dr. Zwickey’s thoughts were then passionately shared back and forth on Facebook and in multiple groups, and as a result her email has been blowing up.

Last week, Dr. Zwickey was featured on Dr. Tyna’s Moore’s “Pain Free & Strong Radio,” in an episode entitled, “Corona Virus with Dr. Heather Zwickey: The Facts from an Immunologist and Infectious Disease Specialist, and just before that, Dr. Zwickey was on the Natural Medicine Journal podcast, discussing “Important Clarifications Regarding COVID-19 and Natural Medicine.” I highly recommend that you take the time to listen to both of these podcasts.

Here’s what Dr. Zwickey shared with her naturopathic physician colleague, verbatim:

I’m hearing a lot of misinformation floating around, so I thought I’d talk about whether or not to use herbs to prevent COVID19. (Everything is referenced.)

 

Prevention: As NDs, you are all aware of how to prevent upper respiratory infections. You’re going to increase Defensins (vitamin D) so that any virus landing on the skin or in the mouth are killed on contact. (1,2)

 

For upper respiratory herbs, I like the combo of 5.   Astragalus (for lungs) is adaptogenic. It reduces inflammation, but can also drive Th1 if you’re exposed to an infection or have lung cancer. It’s also anti-viral. (3,4)

 

Goldenseal and Oregon grape root are directly toxic to viruses (research on flu) and bacteria (think of killing secondary pneumonia). It’s also adaptogenic. It drives Tregs, but can elicit a Th1 response in the right microenvironment. (5,6,7,8,9,10)

 

Echinacea works best at the beginning of an infection and is adaptogenic. Echinacea induces inflammatory cytokines at the beginning of infection and help with resolution post infection. There’s also a meta-analysis showing that it reduces upper-respiratory infections, especially in those susceptible to them. (11,12)

 

Elderberry is also adaptogenic – increasing cytokines in some situations and decreasing them in others. The reason I include it is that it’s anti-viral. There’s research showing it blocks viral uptake. Again, so much research on this that there’s a meta-analysis. (13)

 

I actually developed a supplement with this combo. It’s called Immune and you can find it here: http://www.zamialife.com – not that anyone needs to buy it. You can combine the herbs yourself. It’s just more expensive to buy 5 bottles of herbs.   If people get an infection and you need additional support, Fungi Perfecti has a product called Comprehensive Immune Support that can further increase a Th1 response. (14,15) (The Guggenheim article is about cancer but goes through many of the Th1 stimulating studies.)

 

Do these therapies increase cytokines? Yes. But NOT to the level of cytokine storm. You have to work hard to trigger a cytokine storm. I have not yet seen a situation where an herb can trigger a cytokine storm. We see cytokine storms with super-antigens like staph enterotoxin A, or TSST-1. And in fact, the scientific literature suggests that herbs (including Echinacea) actually decrease cytokine storms. (12,16)

 

So yes, wash hands, don’t touch your face, and sneeze/cough into your elbow. And if you want to use herbs, use what you already know. There is evidence.

 

  1. Pinheiro da Silva F, Machado MCC. Antimicrobial peptides: clinical relevance and therapeutic implications. Peptides. 2012;36(2):308-314. doi:10.1016/j.peptides.2012.05.014
  2. Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J Clin Virol. 2011;50(3):194-200. doi:10.1016/j.jcv.2010.12.006
  3. Li X, Qu L, Dong Y, et al. A Review of Recent Research Progress on the Astragalus Genus. Molecules. 2014;19(11):18850-18880. doi:10.3390/molecules191118850
  4. Hsieh H-L, Liu S-H, Chen Y-L, Huang C-Y, Wu S-J. Astragaloside IV suppresses inflammatory response via suppression of NF-κB, and MAPK signalling in human bronchial epithelial cells. Arch Physiol Biochem. February 2020:1-10. doi:10.1080/13813455.2020.1727525
  5. Yan Y-Q, Fu Y-J, Wu S, et al. Anti-influenza activity of berberine improves prognosis by reducing viral replication in mice. Phytother Res. 2018;32(12):2560-2567. doi:10.1002/ptr.6196
  6. Kim TS, Kang BY, Cho D, Kim SH. Induction of interleukin-12 production in mouse macrophages by berberine, a benzodioxoloquinolizine alkaloid, deviates CD4+ T cells from a Th2 to a Th1 response. Immunology. 2003;109(3):407-414. doi:10.1046/j.1365-2567.2003.01673.x
  7. Cecil CE, Davis JM, Cech NB, Laster SM. Inhibition of H1N1 influenza A virus growth and induction of inflammatory mediators by the isoquinoline alkaloid berberine and extracts of goldenseal (Hydrastis canadensis). Int Immunopharmacol. 2011;11(11):1706-1714. doi:10.1016/j.intimp.2011.06.002
  8. Javadi B, Sahebkar A. Natural products with anti-inflammatory and immunomodulatory activities against autoimmune myocarditis. Pharmacol Res. 2017;124:34-42. doi:10.1016/j.phrs.2017.07.022
  9. Jamshaid F, Dai J, Yang LX. New Development of Novel Berberine Derivatives against Bacteria. Mini Rev Med Chem. January 2020. doi:10.2174/1389557520666200103115124
  10. Qin X, Guo BT, Wan B, et al. Regulation of Th1 and Th17 cell differentiation and amelioration of experimental autoimmune encephalomyelitis by natural product compound berberine. J Immunol Baltim Md 1950. 2010;185(3):1855-1863. doi:10.4049/jimmunol.0903853
  11. Schapowal A, Klein P, Johnston SL. Echinacea reduces the risk of recurrent respiratory tract infections and complications: a meta-analysis of randomized controlled trials. Adv Ther. 2015;32(3):187-200. doi:10.1007/s12325-015-0194-4
  12. Vimalanathan S, Schoop R, Suter A, Hudson J. Prevention of influenza virus induced bacterial superinfection by standardized Echinacea purpurea, via regulation of surface receptor expression in human bronchial epithelial cells. Virus Res. 2017;233:51-59. doi:10.1016/j.virusres.2017.03.006
  13. Hawkins J, Baker C, Cherry L, Dunne E. Black elderberry (Sambucus nigra) supplementation effectively treats upper respiratory symptoms: A meta-analysis of randomized, controlled clinical trials. Complement Ther Med. 2019;42:361-365. doi:10.1016/j.ctim.2018.12.004
  14. Immune Modulation From Five Major Mushrooms: Application to Integrative Oncology. – PubMed – NCBI. https://www-ncbi-nlm-nih-gov.liboff.ohsu.edu/pubmed/26770080. Accessed March 2, 2020.
  15. Antiviral activities of various water and methanol soluble substances isolated from Ganoderma lucidum. – PubMed – NCBI. https://www-ncbi-nlm-nih-gov.liboff.ohsu.edu/pubmed/10624872. Accessed March 2, 2020.
  16. The cytokine storm of severe influenza and development of immunomodulatory therapy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711683/. Accessed March 2, 2020.

Here are some key take-aways and reminders:

  1. At this point (spring, 2020), there are no human trials testing natural medicines against COVID-19, nor are there any registered therapeutics approved by the FDA. (1)
  2. Viruses aren’t actually alive without the use of your cells. (2)
  3. The way that COVID-19 enters the type two pneumocyte is through its S spike protein, which binds to ACE2 receptors. (3) This differentiates it from the average flu, which binds to sialic acid receptors. (4) ACE2 is expressed, for example, in vascular endothelial cells and renal tubular epithelium, and even resides in the gastrointestinal tract and the central nervous system (CNS). (5)
  4. COVID-19 has a furin cleavage site, which allows it to gain entry easily even if a person’s pneumocytes don’t have a lot of ACE2 receptors. (6) By the way, ACE2 inhibitors appear to upregulate ACE2 receptors, though this has not been proven yet.
  5. There are three main reasons the flu is particularly problematic in the winter but this does not seem to matter with COVID-19:
    • Diminished vitamin D exposure and production in the winter (7)
    • Humans are often inside in the winter with recirculated air which increases viral spread
    • Respiratory droplets in the air last longer in cold weather (8)
  6. In the average immune response to a virus, you want a strong Th1 response, which stimulates CD8 and NK cells to kill any virally infected cells. (9,10) Then, you want your immune system to calm down, by stimulating T regulatory cells (T regs). Not having active T regs can be a problem. Hence, you want to have a healthy gut, as an optimized microbiome plays a role in the regulation of T regs early in disease. (11)
  7. Once COVID-19 enters the cell, it stimulates an inflammasome (NLRP3, in particular, with respect to COVID-19), which is the collection of proteins, receptors and mediators involved in inflammation, causing uncontrolled inflammation. (12)
  8. One reason COVID-19 is so deadly is that it causes bilateral pneumonia.
  9. Another reason COVID-19 is so deadly is that people are getting pneumonia in their lower lobes, where fluids pools and then the subsequent pulmonary edema is spiking mortality. (13)
  10. COVID-19 may impact surfactant levels in the lungs, but to what degree this is unknown. Surfactant is responsible for keeping the alveoli open as well as protecting us from secondary infections.
  11. The particular protein made in the cytokine storms that can be induced by COVID-19 is called interleukin-1 beta (IL-1 beta), which drives fever and can mediate fatigue. Coronavirus has two virulence factors, which make it especially deadly, and can lead to a cytokine storm. One of these virulence proteins can trigger the overproduction of interferon-1 beta (IF-1 beta), by basically not allowing the body to turn off the production of IL-1 beta. (14,15)
  12. Three cytokines get activated together, typically, in inflammation, in general: IL-1 beta, IL-6, and TNF-alpha. IL-1, when high, can turn on IL-6, and also it can turn on TNF-alpha. IL-6 is a very strong cytokine, and it is associated with the induction of anxiety, as well as catastrophizing. (16)
  13. According to Dr. Zwickey, some herbs known to lower IL-6 are lemon balm, passionflower, ashwhaghanda, as well as feverfew (17) I was unable to locate studies on lemon balm and passionflower with particular regard to lowering IL-6, but there is limited evidence that rosemarinic acid, which exists in lemon balm, can lower IL-6.
  14. Ibuprofen is problematic because it blocks COX-2 which is in the same pathway as the renin-angiotensin-aldosterone system, which the virus also targets. Acetaminophen (Tylenol) may decrease intracellular glutathione levels in the type II pneumocytes, which are the exact cells targeted by COVID-19. (18)
  15. Hydrotherapy, when increasing core body temperature, motivates the mobilization of immune support to other organs in the body. (19)
  16. The Th1 response responds to viruses and bacteria. But, in asthma, there is a Th2 response going on in the lung, which could potentially “hypothetically” keep the Th1 response under control. Pregnancy also drives a strong Th2 response, which could balance out a Th1 response from the virus. (20)
  17. Melatonin can shut down the inflammasome (NLRP3). (21)
  18. The envelope on the virus makes it easier to kill, because soap and water can destroy it. 70% isopropyl alcocol is better than 100%. It dries out the lipid in the membrane of the virus.
  19. COVID-19 is an RNA virus, like HIV, not a DNA virus, and hence the RNA in the virus itself is more difficult to kill despite the fact it’s lipid membranes are easier to disrupt.
  20. Ascorbic acid or Vitamin C has a ton of literature behind it with regard to respiratory infections and it may be particularly helpful when a person is infected. (22,23)
  21. There are a number of antiviral herbs that are known to be effective, but we don’t yet know if they work particularly on COVID-19.
  22. Vitamins A and D, for example, can support the immune system, and Vitamin C can reduce the specific inflammasome associated with this disease (NLRP3). Melatonin and ascorbic acid both reduce NLRP3. Melatonin levels are inversely correlated with risk, as they can decrease NF-kappa B. (Integrative Considerations during the COVID 3.18.20)

Listen to “EP 86: Corona Virus with Dr. Heather Zwickey: The Facts from an Immunologist and Infectious Disease Specialist” on Spreaker. Resources:

  1. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, Evaluation and Treatment Coronavirus (COVID-19). In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020.
  2. Koonin EV, Starokadomskyy P. Are viruses alive? The replicator paradigm sheds decisive light on an old but misguided question. Stud Hist Philos Biol Biomed Sci. 2016;59:125–134. doi:10.1016/j.shpsc.2016.02.016
  3. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367(6483):1260–1263. doi:10.1126/science.abb2507
  4. Kimble B, Nieto GR, Perez DR. Characterization of influenza virus sialic acid receptors in minor poultry species. Virol J. 2010;7:365. Published 2010 Dec 9. doi:10.1186/1743-422X-7-365
  5. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631–637. doi:10.1002/path.1570
  6. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res. 2020;176:104742. doi:10.1016/j.antiviral.2020.104742
  7. Saraff V, Shaw N. Sunshine and vitamin D. Arch Dis Child. 2016;101(2):190–192. doi:10.1136/archdischild-2014-307214
  8. Lowen AC, Steel J. Roles of humidity and temperature in shaping influenza seasonality. J Virol. 2014;88(14):7692–7695. doi:10.1128/JVI.03544-13
  9. Cook KD, Waggoner SN, Whitmire JK. NK cells and their ability to modulate T cells during virus infections. Crit Rev Immunol. 2014;34(5):359–388. doi:10.1615/critrevimmunol.2014010604
  10. Pallmer K, Oxenius A. Recognition and Regulation of T Cells by NK Cells. Front Immunol. 2016;7:251. Published 2016 Jun 24. doi:10.3389/fimmu.2016.00251
  11. Pandiyan P, Bhaskaran N, Zou M, Schneider E, Jayaraman S, Huehn J. Microbiome Dependent Regulation of Tregs and Th17 Cells in Mucosa. Front Immunol. 2019;10:426. Published 2019 Mar 8. doi:10.3389/fimmu.2019.00426
  12. Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies [published online ahead of print, 2020 Mar 14]. J Biol Regul Homeost Agents. 2020;34(2):1. doi:10.23812/CONTI-E.
  13. Tian S, Hu W, Niu L, Liu H, Xu H, Xiao SY. Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer [published online ahead of print, 2020 Feb 28]. J Thorac Oncol. 2020;S1556-0864(20)30132-5. doi:10.1016/j.jtho.2020.02.010
  14. Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies [published online ahead of print, 2020 Mar 14]. J Biol Regul Homeost Agents. 2020;34(2):1. doi:10.23812/CONTI-E.
  15. Roerink ME, van der Schaaf ME, Dinarello CA, Knoop H, van der Meer JW. Interleukin-1 as a mediator of fatigue in disease: a narrative review. J Neuroinflammation. 2017;14(1):16. Published 2017 Jan 21. doi:10.1186/s12974-017-0796-7
  16. Lazaridou A, Martel MO, Cahalan CM, et al. The impact of anxiety and catastrophizing on interleukin-6 responses to acute painful stress. J Pain Res. 2018;11:637–647. Published 2018 Mar 28. doi:10.2147/JPR.S147735
  17. Pareek A, Suthar M, Rathore GS, Bansal V. Feverfew (Tanacetum parthenium L.): A systematic review. Pharmacogn Rev. 2011;5(9):103–110. doi:10.4103/0973-7847.79105
  18. Dimova S, Hoet PH, Dinsdale D, Nemery B. Acetaminophen decreases intracellular glutathione levels and modulates cytokine production in human alveolar macrophages and type II pneumocytes in vitro. Int J Biochem Cell Biol. 2005;37(8):1727–1737. doi:10.1016/j.biocel.2005.03.005
  19. Mooventhan A, Nivethitha L. Scientific evidence-based effects of hydrotherapy on various systems of the body. N Am J Med Sci. 2014;6(5):199–209. doi:10.4103/1947-2714.132935
  20. Romagnani S. Th1/Th2 cells. Inflamm Bowel Dis. 1999;5(4):285–294. doi:10.1097/00054725-199911000-00009
  21. Favero G, Franceschetti L, Bonomini F, Rodella LF, Rezzani R. Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation. Int J Endocrinol. 2017;2017:1835195. doi:10.1155/2017/1835195
  22. Hemilä H, Douglas RM. Vitamin C and acute respiratory infections. Int J Tuberc Lung Dis. 1999;3(9):756–761.
  23. Vorilhon P, Arpajou B, Vaillant Roussel H, Merlin É, Pereira B, Cabaillot A. Efficacy of vitamin C for the prevention and treatment of upper respiratory tract infection. A meta-analysis in children. Eur J Clin Pharmacol. 2019;75(3):303–311. doi:10.1007/s00228-018-2601-7

 

Can Mouthwash Cause Diabetes?

Can Mouthwash Cause Diabetes?

A 2017 study revealed that the use of mouthwash at least twice daily may be associated with a 50% greater likelihood of developing prediabetes/diabetes (1,2). Say what!? Is it possible that something as simple as swishing Listerine twice a day could double one’s chances of becoming diabetic?

Research into the so-called “salivary nitrate-nitrite-nitric oxide pathway” (3) has led to a growing body of evidence that there may be something to the proposed mechanism of action.

The Salivary Nitrate-Nitrite-Nitric Oxide Pathway

Interestingly, approximately 25% of the nitrate (the other 75% is excreted via the kidneys) that we absorb from our food (mostly from vegetables!) is uptaken by the salivary glands, where it becomes part of the saliva. (4)

This nitrate is then reduced by oral bacteria to nitrite, before it is swallowed and eventually converted to nitric oxide (NO). What is fascinating is that this nitrate helps these oral bacteria to produce energy via respiration in an anaerobic environment. (5)

The Role of Oral Bacteria in Nitric Oxide Production

Little research has been done on the oral microbiome. (6,7) The oral cavity is highly personalized, populated by bacteria strains of Streptococcus, Haemophilus (buccal mucosa), Actinomyces (supragingival plaque), Prevotella (subgingival plaque), and many more. (8)

Using a mouthwash that is “anti-bacterial” or “antiseptic” means that you’ll be indiscriminately laying waste to the good bacteria in your oral microbiome as you attempt to target the so-called bad guys, of which there are few. (9) Ironically, chronic gingivitis, dental caries, and even bad breath result from not having enough of the good guys.

Adding insult to injury, mouthwash is drying to the mouth, which disrupts saliva production. A little known fact is that saliva helps to remineralize the teeth, for example, using nutrient deposits such as phosphorous and magnesium. (10)

Putting The Mouth Back into the Body

The father of modern nutrition, Weston A. Price DDS, observed in his masterpiece, “Nutrition and Physical Degeneration,” that disease could be predicted by the state of oral health in the individual.

He, of course, traveled to many continents and observed dozens of natives in their original habitat, some of whom had not been affected, at least dietarily, by modern industrialized agriculture, which he found wreaked havoc on their oral health (and by extension, their overall health) when subsequently exposed

While disease begins in the gut, according to the father of modern medicine, Hippocrates, the gut does attach to the oral cavity. Perhaps the mouth can be considered to be an extension of the gut?

Nitric Oxide: Another Reason to Eat Your Veggies, Yo!

As a side note, some of the veggies richest in dietary nitrate are garlic and onions, eggplant and squash, arugula, beets, celery and rhubarb.

The Role of Nitric Oxide in Vascular Function

It is well established that nitric oxide (NO) plays an important role in vascular function in the body. (11) Nitric oxide is key to the function of our blood vessels, regulating vascular tone and blood flow, and inducing smooth muscle relaxation and vasodilation.

Without properly functioning blood vessels, hypertension and atherosclerosis are more a likely develop. Reduced levels of nitric oxide are also associated with insulin resistance. In fact, across the board diabetics have reduced levels of nitric oxide in their blood. (12)

What’s in Mouthwash?

If you love mouthwash, why not go with making your own, or at least buying all-natural mouthwash? Of course, it can be tricky figuring out exactly what “all-natural” means.

Mainstream mouthwash, for the most part, is full of artificial flavorings and colorings, with inferior essential oils, industrial chemicals (such as chlorine dioxide, an antibacterial bleaching agent), chlorhexidine (antibacterial and a common allergen) and even detergents such as sodium lauryl sulfate (common in toothpaste and to which many have a sensitivity).

Home-made DIY Mouthwash Recipe

  • Use small glass container, such as mason jar
  • 1.5 TBS baking soda
  • 1 cup distilled water
  • 2 drops tea tree essential oil
  • 2 drops ginger oil
  • 2 drops clove oil
  • 2 drops peppermint, wintergreen, or spearmint essential oil

Shake each time before using, as baking soda settles at bottom of container. Let one tablespoon swish in your mouth for 1-2 minutes. Avoid swallowing, especially when gargling.

Resources

  1. Joshipura KJ, Muñoz-Torres FJ, Morou-Bermudez E, Patel RP. Over-the-counter mouthwash use and risk of pre-diabetes/diabetesNitric Oxide. 2017;71:14-20. doi:10.1016/j.niox.2017.09.004.
  2. Preshaw PM. Mouthwash use and risk of diabetesBritish Dental Journal. 2018;225(10):923-926. doi:10.1038/sj.bdj.2018.1020.
  3. Hezel M, Weitzberg E. The oral microbiome and nitric oxide homoeostasisOral Diseases. 2013;21(1):7-16. doi:10.1111/odi.12157.
  4. Lidder S, Webb AJ. Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathwayBritish Journal of Clinical Pharmacology. 2013;75(3):677-696. doi:10.1111/j.1365-2125.2012.04420.x.
  5. Govoni M, Jansson EÅ, Weitzberg E, Lundberg JO. The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwashNitric Oxide. 2008;19(4):333-337. doi:10.1016/j.niox.2008.08.003.
  6. Gao L, Xu T, Huang G, Jiang S, Gu Y, Chen F. Oral microbiomes: more and more importance in oral cavity and whole bodyProtein & Cell. 2018;9(5):488-500. doi:10.1007/s13238-018-0548-1.
  7. Bars PL, Matamoros S, Montassier E, et al. The oral cavity microbiota: between health, oral disease, and cancers of the aerodigestive tractCanadian Journal of Microbiology. 2017;63(6):475-492. doi:10.1139/cjm-2016-0603.
  8. Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. Defining the Normal Bacterial Flora of the Oral CavityJournal of Clinical Microbiology. 2005;43(11):5721-5732. doi:10.1128/jcm.43.11.5721-5732.2005.
  9. Chino T, Santer DM, Giordano D, et al. Effects of oral commensal and pathogenic bacteria on human dendritic cellsOral Microbiology and Immunology. 2009;24(2):96-103. doi:10.1111/j.1399-302x.2008.00478.x.
  10. Neel EA, Aljabo A, Strange A, et al. Demineralization–remineralization dynamics in teeth and bone. International Journal of Nanomedicine. 2016;Volume 11:4743-4763. doi:10.2147/ijn.s107624.
  11. Loscalzo J, Jin. Vascular nitric oxide: formation and functionJournal of Blood Medicine. 2010:147. doi:10.2147/jbm.s7000.
  12. Tessari P, Cecchet D, Cosma A, et al. Nitric Oxide Synthesis Is Reduced in Subjects With Type 2 Diabetes and NephropathyDiabetes. 2010;59(9):2152-2159. doi:10.2337/db09-1772.