Niacin supplementation may help when NAD+ is low during inflammatory conditions, which might include a viral infection or recovery. This topic was introduced in the recent post Kale & Carrots – super good right? maybe not for everyone. NAD+ levels also tend to be reduced with aging and may be a factor in chronic illness associated with aging. Promoting better NAD+ levels may help protect against aging and chronic illness associated with aging. “NAD+ levels decline during ageing, and alterations in NAD+ homeostasis can be found in virtually all age-related diseases, including neurodegeneration, diabetes and cancer. ” (3)
Providing niacin (6) and niacinamide would be helpful to promote more NAD+ as niacin can be made into the chemical. Preventing breakdown is another way to promote more NAD+. (3) EGCG was mentioned within the reference list of the Kale & Carrots post in some excerpts. EGCG may be able to promote more NAD+ within cells, and a few other flavonoid phytonutrients that may help reduce breakdown of NAD+ by inhibiting the enzymes involved in its metabolism. (7)
EGCG: “NMNATs are also attractive targets for raising NAD+ in cells because they have dual substrate specificity for NMN and nicotinic acid mononucleotide (NaMN), and they contribute to both de novo and salvage pathways (Zhou et al., 2002). The green tea compound epigallocatechin gallate [EGCG]has been reported to activate NMNAT2 by more than 100% and NMNAT3 by 42% at 50 mM, although this needs to be confirmed, as no data were presented in the paper (Berger et al., 2005).” (7)
Pomegranate peel/extract is also a source of EGCG. Pomegranate preparation tips and more information about health benefits is able on page effectivecare.info/G13. Pomegranate. It may have anti-inflammatory activity through down regulation of Fox03a (4) which is a protein that can increase oxidative stress damage in mitochondria (5) where the NAD+ chemical reactions are taking place.
Other phytonutrients may also be helpful to promote NAD+ by decreasing breakdown of it: “An alternative approach to raising NAD+ is to inhibit its degradation either by inhibiting PARPs or NADases, also known as glycohydrolases. The major NADase in mammals, CD38, is inhibited in vitro at low micromolar concentrations by flavonoids including luteolinidin, kuromanin, luteolin, quercetin, and apigenin (IC50 < 10 mM) .” (7)
Luteolinidin is an plant extract (a deoxyanthocyanidin) that is still in research phases for use as a CD38 inhibitor. (1) Kuromanin is also a plant extract, an anthocyanin, available for sale (expensive), under investigation as a CD38 inhibitor (preventing breakdown of NAD+) and neuro protectant. (2)
Luteolin is a flavonoid “found in celery, thyme, green peppers, and chamomile tea,” (18) and “chrysanthemum flowers, sweet bell [green/red/orange] peppers, carrots, onion leaves, broccoli, and parsley [78]. (21)
Quercetin – is in onions, garlic, green leafy veg, citrus peel, figs, and is a focus of several recent posts: Citrus Fig jam: (14), Hesperidin & quercetin content in citrus peel: (15), Decongestant properties of hesperidin/citrus peel: (16).
Apigenin is a flavonoid found in “grapefruit, plant-derived beverages and vegetables such as parsley, onions, oranges, tea, chamomile, wheat sprouts and in some seasonings.” (19) (Intake of more dietary flavonoids on average was associated with a reduced cancer risk. (19))
Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.
Liu S, Zhang X, Sun M, Xu T and Wang A: FoxO3a plays a key role in the protective effects of pomegranate peel extract against amikacin-induced ototoxicity. Int J Mol Med 40: 175-181, 2017 https://www.spandidos-publications.com/10.3892/ijmm.2017.3003
Tseng AH, Shieh SS, Wang DL. SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic Biol Med. 2013 Oct;63:222-34. doi: 10.1016/j.freeradbiomed.2013.05.002. Epub 2013 May 7. PMID: 23665396. https://pubmed.ncbi.nlm.nih.gov/23665396/
Pirinen E, Auranen M, Khan NA, Brilhante V, Urho N, Pessia A, Hakkarainen A, Kuula J, Heinonen U, Schmidt MS, Haimilahti K, Piirilä P, Lundbom N, Taskinen MR, Brenner C, Velagapudi V, Pietiläinen KH, Suomalainen A. Niacin Cures Systemic NAD+ Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy. Cell Metab. 2020 Jun 2;31(6):1078-1090.e5. doi: 10.1016/j.cmet.2020.04.008. Epub 2020 May 7. Erratum in: Cell Metab. 2020 Jul 7;32(1):144. PMID: 32386566. https://pubmed.ncbi.nlm.nih.gov/32386566/
Pomegranate peel extract has been found helpful at preventing access of the SARS-CoV-2 virus to ACE2 receptors in a cell based study (in vitro). The pomegranate peel extract would contain mixed plant phytonutrients that might include EGCG, ellagitannins and gallotannins. The extract also inhibited “the activity of thevirus 3CL protease.” (Tito, et al, 2020)
“In this study, by using different in vitro approaches, we uncovered the role of a pomegranate peel extract in attenuating the interaction between the SARS-CoV-2 Spike glycoprotein and the human Angiotensin-Converting Enzyme 2 (ACE2) receptor, and in inhibiting the activity of the virus 3CL protease.” (Tito, et al, 2020)
Ellagitannins and gallotannins are hydrolyzable tannins and have been found to have anti-viral effects against the herpes simplex virus. (search results ellagitannins antiviral)
Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.
Reference List
(Tito, et al, 2020) Tito A, Colantuono A, Pirone L, et al., (2021) A pomegranate peel extract as inhibitor of SARS-CoV-2 Spike binding to human ACE2 (in vitro): a promising source of novel antiviral drugs. bioRxiv 2020.12.01.406116; doi: https://doi.org/10.1101/2020.12.01.406116 Frontiers in Chemistry, Vol 9, DOI=10.3389/fchem.2021.638187, ISSN=2296-2646 https://www.frontiersin.org/articles/10.3389/fchem.2021.638187/full
The take home point about retinoid toxicity that is mind blowing to this dietitian (last post, & second half of this post) is that kale and carrots and other super nutritious beta-carotene rich foods might be part of the health problem for some people. If retinoid toxicity is occurring due to an enzyme change in the liver then the long held belief that we can’t really overdose on the carrot type of vitamin A may be wrong. Carnivore diet followers though, don’t rejoice too quickly, the animal product foods are sources of the active form of vitamin A and would definitely be part of the problem if excessive retinal was being activated to retinoic acid.
Thanks to everyone who responded to my survey on retinoid toxicity (last post/document). The summary points are that dry skin, seasonal allergies, and fibromyalgia type fatigue are fairly common symptoms and 100% of respondents (including me) were unfamiliar with all of the symptoms. Rewriting the survey and getting approval for research is needed. The initial effort did show that the topic is an unfamiliar one.
Change in the gene expression of enzymes involved in retinal/retinoic acid metabolism has been seen with infection with the Epstein Barr virus. (11) Chronic symptoms for years after an Epstein Barr infection have been known. The range of symptoms that can be due to retinoid toxicity could confuse the diagnosis process – see a dermatologist for the skin, an autoimmune/allergy specialist and a general practitioner might also be involved – would any one of them ask about all the possible retinoid toxicity symptoms? or suggest cutting back on food and supplement sources of vitamin A/beta carotene in order to just test the theory and see if any symptoms improve?
Retinoid toxicity may also help explain why smoking tobacco seems to have a somewhat protective effect against peripheral neuropathy while also being a risk – NAD+ deficiency could mean nicotine is helping provide a source of niacin – so the take home point there would be take niacin to help prevent nerve damage and fatigue (1, 2, 3) without providing smoke toxins that also worsen health risks. (post: Neuropathy can be a cause of extreme tiredness)
Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide involved in energy production within the mitochondria of cells and is protective against harmful effects of oxidative stress ( 2) – the chemical effects of physical or emotional stressors on the body. NAD+ is used in one enzyme involved in vitamin A metabolism. (9)
The following video connects Mast Cell over activity with niacin deficiency. Retinoic acid would add to mast cell activity as it is an activator of mast cells too. Mast cells can release histamine & then there can also be more supplied from foods, or produced in response to foods in mast cells in the intestinal lining. If the Epstein Barr virus causes retinoic acid metabolism gene changes maybe other infections can too. See: First Effective Treatment for Long Covid | Stunning Data from Huge New Study Dec 22, 2020 youtube.com, https://youtu.be/9-3V3h0ncIA
Anti-histamine medications, over-the-counter generally
Prescription medications. Possibly ACE1 and ACE2 blockers, or Mast cell stabilizers or inhibitors.
The chemistry is complex, I am still learning, in the meantime though, cutting back on my daily intake of carrots, kale and then the addition of a lot of mango for a while – DID HELP – when did I ever think that I might be eating too much kale? or mango or my favorite anti-cancer vegetable – the carrot? answer – never. Learning about retinoid toxicity has been unexpected but helpful. Again carnivore diet fans – earlier in my symptom flare up history I found I had to cut out all animal products from my diet in order to get the new skin problem to resolve. Retinoid toxicity may have been a factor that I reduced without realizing why it helped but it worked so I stuck with it.
From a differential diagnosis perspective the range of symptoms that can be a result of retinoid toxicity would likely not be connected to each other. The patient might be seeing an allergy and autoimmune specialist, a psychiatric medical professional and talk therapist, and a general practitioner and as problems worsened a liver specialist, kidney specialist, and a neurologist might be added to the medical team – would they all talk to each other about the amount of carrots and liver in the patient’s average daily diet?
Celebrating a new year and new health discoveries! (image: fireworks)
Excerpt from previous post – sources/types of vitamin A & retinoic acid
Might an excess or retinoic acid be overstimulating activity in the brain and causing hyperexcitability? (1, 2) Excess retinoic acid can have negative effects in the brain, particularly the hippocampus, (6), the area damaged initially in Alzheimer’s dementia, and may cause cell death. (7)
“The three active forms of vitamin A in the body are retinol, retinal, and retinoic acid.” … “Retinol and retinyl esters are often referred to as preformed vitamin A. Retinol can be converted by the body to retinal, which can be in turn be oxidized to retinoic acid, the form of vitamin A known to regulate gene transcription. Retinol, retinal, retinoic acid, and related compounds are known as retinoids. β-Carotene and other food carotenoids that can be converted by the body into retinol are referred to as provitamin A carotenoids (see the article on Carotenoids). ” (11)
Malfunction of CYP enzymes could increase the risk of excess retinoic acid as they are required to break down the active forms of vitamin A. (12)
Beta-carotene food sources
Beta-carotene, is an inactive form of vitamin A that is generally considered non-toxic, it provides the orange color of carrots, and since it is a fat soluble nutrient it can collect within our skin if eaten in excess and cause an orange color to the skin. (8, 13) It is unlikely to eat enough of the nutrient to cause the skin color change unless regularly drinking juice made with carrots, or kale or other fruits and vegetables that are very rich in beta- carotene. It is unlikely to cause any health problems other than to appear orange for a while (stop drinking so much carrot juice to make it fade). Infants and toddlers who are fed limited numbers of foods but daily may also develop the problem if carrots and sweet potatoes are given consistently instead of including more variety.
Beta-carotene may be broken down to the active retinal form in the intestinal lining or in the liver. (13)
Sources of Pre-formed vitamin A and Provitamin A – beta-carotene and other carotenoids.
“…vitamin A toxicity can occur from either topical or oral use. Oral vitamin A delivery comes in two forms: provitamin A (a prodrug that is metabolized to vitamin A) and preformed vitamin A. Pre-formed vitamin A is obtained from animal food sources, including dairy products and liver, and in most supplements. A list of other foods containing Vitamin A includes milk, cheese, margarine, butter, eggs, chicken, chicken liver, beef, beef liver, processed meats, pizza, fish, and cold breakfast cereals[1]. Provitamin A (beta-carotene and other carotenoids), found in plants such as green leafy vegetables, sweet potatoes, and carrots, must be metabolized to vitamin A. As a result, it is less likely to cause toxicity.” (9) [See Reference list from previous post/document)
From the survey:
Meals and snacks include meats, poultry, fish, milk and other dairy products. [and Vitamin A & D fortified milk equivalent drinks]
Several servings per day typically
At least one serving per day
At least one serving per week
One serving per month or less
No servings of animal products typically
Unknown
Meals and snacks include carrots, tomato products (fresh, or tomato sauce, ketchup, or salsa), sweet potatoes, winter squash or pumpkin, dark green leafy vegetables, cantaloupe, apricots, mango, papaya, peaches, nectarines.
Several servings per day typically.
At least one serving every other day
At least one serving per week
One serving or less per month
No servings of carotenoid rich plant foods typically
*2. Answer 2 is the amount menu planners have as a minimum goal – 1 beta carotene rich produce serving at least every other day.
My own symptoms & diet: I was having several servings of beta carotene rich foods daily and often several times a day, when I had a skin symptom flare up, reducing to the less frequent use helped the skin problem, cheilitis, finally get better. Cheilitis is nonhealing cracks/fissures at the corners of the lips and my problem didn’t get better with more vitamin Bs or iron which deficiencies of can also be a cause., but then got better within a few days of stopping the daily carrot, kale and mango intake. I have one serving occasionally now instead of several daily.
Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.
Reference List – includes excerpts & references not mentioned in the text.
Braidy N, Villalva MD, van Eeden S. Sobriety and Satiety: Is NAD+ the Answer?. Antioxidants (Basel). 2020;9(5):425. Published 2020 May 14. doi:10.3390/antiox9050425 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278809/
Griffith GD, Griffith T, Byerrum RU, Nicotinic Acid as a Metabolite of Nicotine in Nkotiana rustica.* J of Biological Chemistry, Vol. 226, No. 12, December 1960 https://www.jbc.org/content/235/12/3536.full.pdf “It appears that the nicotinic acid derived from nicotine enters the metabolic pool and presumably is converted to bound forms such as the pyridine nucleotides, since the dilution of isotope increases somewhat with time.“
Pirinen E, Auranen M, Khan NA, Brilhante V, Urho N, Pessia A, Hakkarainen A, Kuula J, Heinonen U, Schmidt MS, Haimilahti K, Piirilä P, Lundbom N, Taskinen MR, Brenner C, Velagapudi V, Pietiläinen KH, Suomalainen A. Niacin Cures Systemic NAD+ Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy. Cell Metab. 2020 Jun 2;31(6):1078-1090.e5. doi: 10.1016/j.cmet.2020.04.008. Epub 2020 May 7. Erratum in: Cell Metab. 2020 Jul 7;32(1):144. PMID: 32386566. https://pubmed.ncbi.nlm.nih.gov/32386566/
Luis Rajman, Karolina Chwalek, and David A. Sinclair https://www.cell.com/cell-metabolism/pdf/S1550-4131(18)30122-0.pdf “NMNATs are also attractive targets for raising NAD+ in cells because they have dual substrate specificity for NMN and nicotinic acid mononucleotide (NaMN), and they contribute to both de novo and salvage pathways (Zhou et al., 2002). The green tea compound epigallocatechin gallate has been reported to activate NMNAT2 by more than 100% and NMNAT3 by 42% at 50 mM, although this needs to be confirmed, as no data were presented in the paper (Berger et al., 2005). … An alternative approach to raising NAD+ is to inhibit its degradation either by inhibiting PARPs or NADases, also known as glycohydrolases. The major NADase in mammals, CD38, is inhibited in vitro at low micromolar concentrations by flavonoids including luteolinidin, kuromanin, luteolin, quercetin, and apigenin (IC50 < 10 mM) .” …niacin/niacinamide supp may help reduce risk of kidney injury which involves low NAD+ … bloodflow and muscle and nerve function also may be improved by adequate niacin treatment. … “Since then, numerous studies have reinforced the view that NAD+ levels are key to neuronal function and survival. This includes the dependence on NMNAT2 and its NAD synthesis activity for axonal survival (Yan et al., 2010). ” Supplementing may help protect against Parkinson’s Disease and Alzheimer’s dementia and other neurologic conditions. “NAD-boosting regimens prevent and in some cases can reverse neuronal degeneration associated with hearing loss, prion toxicity, retinal damage, traumatic brain injury (TBI), and peripheral neuropathy (Brown et al., 2014; Dutca et al., 2014; Hamity et al., 2017; Lin et al., 2016; Vaur et al., 2017; Yin et al., 2014; Zhou et al., 2015) ” https://www.cell.com/cell-metabolism/pdf/S1550-4131(18)30122-0.pdf
Fricker RA, Green EL, Jenkins SI, Griffin SM. The Influence of Nicotinamide on Health and Disease in the Central Nervous System. Int J Tryptophan Res. 2018;11:1178646918776658. Published 2018 May 21. doi:10.1177/1178646918776658 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966847/
Seung-Hye Hong, Ho-Phuong-Thuy Ngo, Hyun-Koo Nam, Kyoung-Rok Kim, Lin-Woo Kang, Deok-Kun Oh. Alternative Biotransformation of Retinal to Retinoic Acid or Retinol by an Aldehyde Dehydrogenase from Bacillus cereus, Applied and Environmental Microbiology Jun 2016, 82 (13) 3940-3946; DOI: 10.1128/AEM.00848-16 https://aem.asm.org/content/82/13/3940 “This enzyme converted not only small aldehydes to carboxylic acids but also the large aldehyde all-trans-retinal to all-trans-retinoic acid with NAD(P)+.“
Jones RJ, Dickerson S, Bhende PM, Delecluse HJ, Kenney SC. Epstein-Barr virus lytic infection induces retinoic acid-responsive genes through induction of a retinol-metabolizing enzyme, DHRS9. J Biol Chem. 2007 Mar 16;282(11):8317-24. doi: 10.1074/jbc.M608667200. Epub 2007 Jan 22. PMID: 17244623. https://www.jbc.org/content/282/11/8317.long “Abstract: Lytic Epstein-Barr virus (EBV) replication occurs in differentiated, but not undifferentiated, epithelial cells. Retinoic acid (RA) induces epithelial cell differentiation. The conversion of retinol into its active form, retinoic acid, requires retinol dehydrogenase enzymes. Here we show that AGS gastric carcinoma cells containing the lytic form of EBV infection have enhanced expression of a gene (DHRS9) encoding an enzyme that mediates conversion of retinol into RA. DHRS9 expression is also increased following induction of lytic viral infection in EBV-positive Burkitt lymphoma cells. We demonstrate that the EBV immediate-early protein, BZLF1, activates the DHRS9 promoter through a direct DNA binding mechanism. Furthermore, BZLF1 expression in AGS cells is sufficient to activate DHRS9 gene expression and increases the ability of retinol to induce the RA-responsive gene, CYP26A1. “
The second half of this post goes into more detail about retinoid toxicity. Retinoid acid is an active form of vitamin A and it can activate mast cells of the immune system and is involved in many other functions of the body including skin health and calcium balance. The activation of mast cells can affect mood by increasing histamine release which affects brain excitability. Mast Cell Activity & Hyperexcitable Mood.
If the theory about retinoic acid is correct, then the liver is overactivating too much vitamin A and a solution for reducing symptoms might involve significantly reducing vitamin A sources in the diet. Adding liver healing nutrients and herbs might also be part of a solution aimed at restoring normal function and avoiding other mast cell activating foods or histamine releasing foods might also be part of a symptom resolution process.
This is complex physiology. Gathering more information from many people can help to show whether there is a pattern connecting excess vitamin A/retinoic acid and vaccine or medication injury.
Thanks in advance for completing the survey.
Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.
