Pomegranate and Covid19/spike

A collection of CoV links about pomegranate and hyperinflammation, more recent than my webpage on effectivecare.info: G13. Pomegranate.

Topics included are ACE2 protection, inhibition of NET formation and NLRP3 inflammasomes (allergy/autoimmune killer cells promoted by CoV spike), other phytonutrients that also inhibit inflammasome production or promote p53, and pomegranate and other phytonutrients that promote NAD+, which is reduced by spike/CoV. NAD+ is part of niacin and energy metabolism.

ACE2 protection of the receptor and its function:

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 the virus 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)

Inhibit NET formation:

"We could show that the flavonoids (−)-epicatechin, (+)-catechin hydrate, and rutin trihydrate as well as vitamin C and the pharmacological substances N-acetyl-L-cysteine and 5-aminosalicylic acid inhibited PMA induced ROS production and NET formation." (Kirchner, et al, 2013)

Why care about NET formation? because it may be associated with worse risk of coagulation and blood clots forming in severe COVID-19 illness. ((Thierry and Roch, 2020), (Kiefer, 2020) Interleuken-6 (IL-6) can increase NET formation by neutraphil white blood cells attempting to ensnare pathogens and IL-6 levels tend to be elevated in more severe COVID-19 illness.

NET-neutraphil extracellular traps: "Thrombosis [coagulation/blood clotting], sepsis, and thick mucous secretions share neutrophil extracellular traps as a common causal agent. In addition to phagocytosis and degranulation, neutrophils can kill pathogens by extruding neutrophil extracellular traps (NETs), a process termed NETosis." (Yanuck, et al)

Rutin is found in citrus peel and other plants. Epicatechin and catechin hydrate are in pomegranate peel or juice possibly (more in the peel). N-acetyl-L-cysteine is available as a supplement also known as NAC, and 5-aminosalicylic acid is a medication. Acetylsalicylic acid is aspirin and it also inhibits NET formation. (search results) Salicylic acid may be in some spices/plant foods. Many spices used in Indian cooking are good sources of salicylic acid. (post: Carrots, Spices, and baby aspirin help prevent cancer)

NLRP3 Inflammasomes inhibition:

Inhibiting NET formation helps prevent killer inflammasomes from being made.

NLRP3 Inflammasomes are complex units that are built within cells in response to signals from the innate immune system called cytokines. The inflammasomes release even more cytokines that lead to death of the cell by pyroptosis - since the cell is assumed to be infected and would then be in need of removal from the body. When our cells are in trouble from infection, cancerous changes, or simply aging, they add surface marker proteins that signal to the immune system - 'trouble here - my time is up, remove me please, for the purpose of the greater good'. In allergies or autoimmune antibody reactions - the trouble signals are actively calling for the creation of NLRP3 Inflammasomes, but there isn't really trouble in the cell. If an NLRP3 Inflammasome had been constructed though, the cell will still be killed by pyroptosis - it was signaled for and the chemicals lined up, so to speak, and did their job. (He, et al, 2015) (Iorga and Dara, 2019)

"NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death." (Swanson, Deng, Ting, 2019)

The inflammatory cytokines also cause other symptoms that might help remove a pathogen if sick, but during allergy season, the symptoms may just be emptying the tissue box. NLRP3 Inflammasomes may also be involved in allergies developing - sensitivities being created in the first place. (Xiao, Xu, Su, 2018) The risk of allergy sensitivities or autoimmune antibodies being created would be worse for people with low vitamin D levels or low magnesium. Magnesium is needed in the metabolism of vitamin D.

The SARS-CoV-2 virus spike protein, the E protein section, causes activation of NLRP3 Inflammasome creation, and resulting increase in inflammation can also signal further creation of them:

"The IC activity of E protein [168] as well as those of the other accessory viroporins, 3a and 8a [160], activate the NLRP3 inflammasome by effluxing Ca2+ from the lumen of the ER/ERGIC/Golgi, altering the homeostatic levels of cytosolic Ca2+ [168,180] and resulting in upregulation and secretion of pro-inflammatory TNF-α, IL-1β, IL-6 and IL-18 [160,181]. ER stress [182] and ROS production [183] are also activators of the NLRP3 inflammasome, and due to E protein’s regulation of ER stress they may also activate NLRP3 through an alternative mechanism." (Wong and Saier, 2021)

NLRP3 Inflammasomes are little killing machines that we need when a cell is infected, but which become very damaging if they are being created in response to an allergy or autoimmune type of reaction. Immunomodulating phytonutrients can help the body by rebalancing an over-active or under-active immune response making them generally safe for use. For more information about immunomodulators see: Artemisinin, arteannuin-B, sgp130Fc and COVID-19.

Who is most at risk for an immune reaction? People low in vitamin D, zinc, selenium, B vitamins, and others.

Cells from people who had been sick with COVID-19 reacted to exposure to the SARS-CoV-2 spike protein and inflammasome production occurred. Cells from people who had not been pre-exposed to SARS-CoV-2 did not react to cause inflammasome creation:

"Here we show that the SARS-CoV-2 spike protein (S-protein) primes inflammasome formation and release of mature interleukin-1β (IL-1β) in macrophages derived from COVID-19 patients but not in macrophages from healthy SARS-CoV-2 naïve individuals." (Theobald, et al, 2021)

Which suggests that an allergy like sensitization to the S-protein occurred

Anti-inflammatory Phytonutrients/nutrients from a previous post; promote p53 or inhibit NLRP3:

Other phytonutrients including quercetin which is found in citrus peel, also can help inhibit production or activity of the inflammatory NLRP3 inflammasome which has been found to be elevated during more severe COVID19 illness. Sulfarophane (broccoli, etc), resveratrol (grape skins, etc), EGCG (green tea, pomegranate peel), curcumin (turmeric/curry powder), gensenoside (ginseng), emodin (aloe vera gel), mangiferin (mango) and genipin (from a fruit used as a Traditional Chinese Medicinal) are also phytonutrients that may reduce activity or production of NLRP3 inflammasomes. (17*) **

Increasing activity of a protein called p53 seems to help inhibit the production or activity of the NLRP3 inflammasome. Phytonutrients and nutrients that may promote p53 activity also include zinc, artemisinin (wormwood herb), goldenseal (berberine, also found in a few other herbs), Black seed oil (Nigella sativa), ginger (6-gingerol), feverfew, chamomile, and cordyceps mushrooms. (18*)** Replication of human coronaviruses and the SARS-CoV-1,(2003 strain) virus has been found to be inhibited by p53 and have also been found to cause the production of an additional protein that leads to breakdown of the p53 protein which may help explain the dysfunction of immune function in more severe infections. (21*, 22*)**

• For more about p53 and how it may help against aging see: Intermittent fasting, magnesium, cancer prevention, and elephants - "Elephants never forget" - it may be because of their p53 gene.

Inactivating the NLRP3 inflammasome seems to have anti-inflammatory benefits (17*) that may help prevent age related changes. It is an area of research being pursued for pharmaceutical development. (11*)** Sleep masks/pitch blackness during sleep, with the alarm clock and light leaking in the window covered, could help your body inactivate the NLRP3 inflammasome on a nightly basis with no ongoing copay (by increased melatonin production, see: Sleep and health, for tips for improving sleep habits for better melatonin production). **( Excerpt from: Bitter Taste Receptors… see for references 11*, 17*, 18*, 21*, 22*) *The excerpt was included in: Phytonutrients that may help against SARS-CoV-2 & jenniferdepew.com/Phytonutrients.

The NLRP3 Inflammasome & Spike Protein information is from a longer post with more information about pyrotopsis.

Pomegranate Peel may help increase NAD+

- EGCG and other phytonutrients that promote NAD+ are included in this post. (transcendingsquare.com)

• 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).” (Rajman, Chwalek, Sinclair, 2018)

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) .” (Rajman, Chwalek, Sinclair, 2018)

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).” (Rajman, Chwalek, Sinclair, 2018)

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) ” (Rajman, Chwalek, Sinclair, 2018)

Phases of illness:

Different treatments may be needed for different phases of illness and inflammation. "…interventions for one phase may not be appropriate for a different phase. The 4 phases addressed are: Prevention, Infection, Inflammation & Recovery." (Yanuck, et al) Pomegranate products can help with all phases of illness.

G13. Pomegranate (effectivecare.info).

The yellowish color may mean the peel has less carotenoids in ratio to anthocyanidins. It has more carotenoids and chlorophyll during the unripe green stage. (Zhao, et al, 2015) Photo by Robert Anasch on Unsplash

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

(He, et al, 2015) He, Wt., Wan, H., Hu, L. et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res 25, 1285–1298 (2015). https://doi.org/10.1038/cr.2015.139 https://www.nature.com/articles/cr2015139

(Iorga and Dara, 2019) Andrea Iorga, Lily Dara, Chapter Two - Cell death in drug-induced liver injury, Editor(s): Anup Ramachandran, Hartmut Jaeschke, Advances in Pharmacology, Academic Press, Volume 85, 2019, Pages 31-74, ISSN 1054-3589, ISBN 9780128167595, https://doi.org/10.1016/bs.apha.2019.01.006. https://www.sciencedirect.com/science/article/abs/pii/S1054358919300067 Excerpt viewable here: https://www.sciencedirect.com/topics/neuroscience/pyroptosis

(Kiefer, 2020) Julie Kiefer, Clues to COVID-19 Complications Come from NET-Like Inflammatory Response. Jun 29, 2020, healthcare.utah.edu, https://healthcare.utah.edu/publicaffairs/news/2020/06/nets-covid.php

(Kirchner, et al, 2013) Kirchner T, Hermann E, Möller S, et al. Flavonoids and 5-aminosalicylic acid inhibit the formation of neutrophil extracellular traps. Mediators Inflamm. 2013;2013:710239. doi:10.1155/2013/710239 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871909/

(Rajman, Chwalek, Sinclair, 2018) Luis Rajman, Karolina Chwalek, and David A. Sinclair, Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence, Cell Metabolism Review, 27, March 6, 2018, pp 529-547, https://www.cell.com/cell-metabolism/pdf/S1550-4131(18)30122-0.pdf

(Swanson, Deng, Ting, 2019) Swanson, K.V., Deng, M. & Ting, J.PY. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19, 477–489 (2019). https://doi.org/10.1038/s41577-019-0165-0 https://www.nature.com/articles/s41577-019-0165-0

(Theobald, et al, 2021) Theobald SJ, Alexander Simonis A, Theodoros Georgomanolis T, et al., Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19, EMBO Mol Med (2021) e14150. https://doi.org/10.15252/emmm.202114150 https://www.embopress.org/doi/full/10.15252/emmm.202114150

(Thierry and Roch, 2020) Thierry AR, Roch B. SARS-CoV2 may evade innate immune response, causing uncontrolled neutrophil extracellular traps formation and multi-organ failure. Clin Sci (Lond). 2020 Jun 26;134(12):1295-1300. doi: 10.1042/CS20200531. PMID: 32543703. https://pubmed.ncbi.nlm.nih.gov/32543703/

(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

(Wong and Saier, 2021) Wong, N.A. and Saier, Jr., M. H., The SARS-Coronavirus Infection Cycle: A Survey of Viral Membrane Proteins, Their Functional Interactions and Pathogenesis. Int. J. Mol. Sci. 2021, 22, 1308. https://doi.org/10.3390/ijms22031308 https://www.dropbox.com/s/kfnfxn99h5k6hxq/ijms-22-01308-v3%20%281%29.pdf?dl=0 *Quote from page 20

(Xiao, Xu, Su, 2018) Xiao Y, Xu W, Su W. NLRP3 inflammasome: A likely target for the treatment of allergic diseases. Clin Exp Allergy. 2018 Sep;48(9):1080-1091. doi: 10.1111/cea.13190. Epub 2018 Jul 3. PMID: 29900602. https://pubmed.ncbi.nlm.nih.gov/29900602/

(Yanuck, et al) Yanuck SF, Pizzorno J, Messier H, Fitzgerald KN, Evidence Supporting a Phased Immuno-physiological Approach to COVID-19 From Prevention Through Recovery. athmjournal.com/ https://athmjournal.com/covid19/research/evidence-supporting-a-phased-immuno-physiological-approach-to-covid-19-from-prevention-through-recovery/

(Zhao, et al, 2015) Zhao, Xueqing & Yuan, Zhaohe & Yin, Yanlei & Feng, Lijuan. (2015). Patterns of pigment changes in pomegranate (punica granatum l.) peel during fruit ripening. Acta Horticulturae. 1089. 83-89. 10.17660/ActaHortic.2015.1089.9. https://www.researchgate.net/publication/282437619_Patterns_of_pigment_changes_in_pomegranate_punica_granatum_l_peel_during_fruit_ripening