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HOW TO BOOST YOUR IMMUNE SYSTEM AND MODULATE THE CYTOKINE STORM IN VIRAL INFECTIONS

Updated: May 11, 2020



HOW TO BOOST YOUR IMMUNE SYSTEM

AND MODULATE THE CYTOKINE STORM

IN VIRAL INFECTIONS


Based on "Natural Approches to health & immunity" by Dr. Rober G. Silverman and numerous medical researches.

Coronavirus disease (COVID-19) is an infectious disease caused by a new coronavirus SARS-CoV-2.

Most people infected with the COVID-19 virus will experience mild to moderate respiratory illness. Older people, and those with underlying medical problems like cardiovascular disease, diabetes, chronic respiratory disease, and cancer are more likely to develop serious illness.

Factors that make us more likely to cotract COVID-19.

- cardiovascular disease

- diabetes

- age

- hypertension

- obesity

- chronic pulmonary disease

- chronic liver or kidney disease

- autoimmune conditions

- chronic neurological diseases

Statistics about comorbidities show that 71% of those hospitalized with COVID - 19 in the United States and 78% of those in intensive care have underlying health conditions like: diabetes, heart disease, chronic lung disease.


CDC.gov. March 28, 2020


COVID-19 is associated with high inflammatory burden that can induce vascular inflammation myocarditis and cardiac arrhythmia.


Tao G, Yong Zhen F, Ming C, et al. JAMA Cardiol, Mar 27, 2020 online


Loss of smell or taste might be early sign of infection with coronavirus SARS-CoV2.


New Study on COVID-19 Estimates 5.1 Days for Incubation Period.





97.5 percent of people develop symptoms of SARS-CoV-2 infection within 11.5 days of exposure.


Ann Intern Med. Published online March 10, 2020 Johns Hopkins. Published online March 9, 2020



Ibuprofen is not recommended for using for COVID-19 because is damaging the gut lining and the tight junction of blood-brain barrier. Ibuprofen increases also Angiotensin-converting enzyme 2 (ACE2).


Angiotensin-converting enzyme 2 (ACE2) is an enzyme attached to the outer surface of cells in the lungs, heart, arteries, kidney and intestines. ACE2 lowers blood pressure. ACE2 also serves as the entry point into cells for some coronaviruses.


Coronavirus symptoms:


- fever

- cough

- fatigue

- dyspnea

- sputum production

- shortness of breath

- myalgia

- chill

- diziness

- headache

- sore throat

- nausea or vomiting

- diarhoea

- nasal congestion





Eye ocular abnormalities can appear also in COVID-19 patients, involving the eye conjunctivitis, conjunctival hyperemia, epiphora, chemosis, and increased secretions

It means that ocolar abnormalities repeatedly occurred in patients with more severe

COVID-19.


Wu P, Duan F, Luo C, et al. Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China. JAMA Ophthalmol. Published online March 31, 2020

Why does SARS-CoV-2 spread so easily?


Corovirus can make 10,000 copies of itself just in hours. It causes that within a few days, infected pacient can have hundreds o millions of viral particles in every teaspoon of blood.



ACE-2 is the host cell receptor responsible for mediating infection by SARS-CoV-2 -coronavirus responsible for COVID19.

SARS-CoV-2 has a specific structure that allows it to bind at least 10 times more tightly than the corresponding spike protein of SARS-CoV to their common host cell receptor.

SARS-CoV-2 binds to ACE2 with higher affinity than other coronaviruses. This is one of reasons why SARS-CoV-2 binds 10 times more tightly to host cells than SARS-CoV.

Treatment with anti-ACE-2 antibodies disrupts the interaction between virus and receptor.





Fecal and oral transmission


Fecal and oral transmission may be part of COVID-19 clinical picture.

10% of of coronavirus patients have GI symptoms: diarrhea, nausea, vomiting, and/or abdominal discomfort before onset of respiratory symptoms.

Researchers found that RNA and proteins from SARS-CoV-2 (viral cause of COVID-19) are shed in feces early in infection and persist after respiratory symptoms abate.

GI manifestations consistent with distributor of ACE2 receptors which serve as entry points for SARS-CoV-2.

Receptors – most abundant in cell membranes of lung AT2 cells as well as in enterocytes in the ileum and colon.


GI track is possible route of viral transmission:


• 53.4% of patients had SARS-CoV-2 RNA in stool

• 23% of patients tested positive in stool despite testing negative for the virus in respiratory samples

• Some of clinical evidence indicates digestive system may serve as an alternative route of SARS-CoV-2 infection

• In addition to respiratory track, clinicians should be careful to promptly identify the patients with initial GI symptoms


Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2, Gastroenterology, Feb. 27, 2020 online

GUT-LUNG CONNECTION

Dr. Rob’s GUT MATRIX




"Your gut is not Las Vegas. What happens in the gut does not stay in the gut" - Dr. Alessio Fasano (Italian medical doctor, pediatric gastroenterologist, and researcher). What happens in the gut, doesn’t stay in the gut. ⠀⠀⠀⠀⠀⠀⠀⠀⠀ The gut affects your brain, thyroid, lung, liver, digestion, immunity, weight, skin, etc.

GUT-LUNG CONNECTION


Lungs should be considered as an ecosystem with its own microbiota.





Some probiotics show beneficial effect on lung health and treat respiratory disease.

The gut and lung microbiota are clearly linked by nutrition and immune system.


Mathieu E, Escribano-Vazquez U, Descamps D, et al. Frontiers in Physiology, 2018;9:1168

Negi S, Pahari S, Bashir H, Agrewala JN. Frontiers in Immunology, 2019;10:1142

Zhu X, Han Y, Du J, et al. OncoTarget. 2017 May 10;8(32):53829-53838

Gut-lung communication


The gut microbiota feeds and matures the intestinal epithelium and is involved in immunity, when the principal role of the lung microbiota seems to be the orientation and balance of aspects of immune and epithelial responsiveness. This implies that the local and remote effects of bacterial communities are likely to be determinant in many respiratory diseases caused by viruses, allergens or genetic deficiency.




The Gut-Lung Axis


The gut–lung axis or GLA has emerged as a specific axis with intensive dialogues between the gut and lungs and comprises the anatomical, systemic, and nervous system connections mediating reciprocal exchanges of microbial signals between the lungs and the gut. One of the connections between the gut and the lung involves the translocation of bacteria via oropharynx reflux. The human body experiences multiple reflux events (especially in pathological conditions) that can transport different bacterial communities from the digestive tract to the upper respiratory tract. The bacteria can be then translocated to the lungs by micro-aspiration. Bacteria and bacterial fragments may also be translocated in the lymph and blood, because the lymph and blood play a significant role in the migration of immune cells to distal sites.


Mathieu E, Escribano-Vazquez U, Descamps D, et al. Frontiers in Physiology, 2018;9:1168



Bidirectional Gut-Lung Axis

Enaud R, Prevel R, Ciarlo E, et al. Frontiers in Cellular and Infection Microbiology, 2020;10:9

Schematic representation to depict assimilation of dietary nutrients by gut microbiome and their impact on distal organs




Anand S, Mande SS. Frontiers in Microbiology, 2018;9:2147



Pulmonary microbiome in health and critical illness


Lung and gut microbiomes undergo profound changes in critically ill patients. Lung microbiome might become enriched with gut-associated microbes as demonstrated in acute respiratory distress syndrome (ARDS) and sepsis. In these conditions, bacteria from the gut might enter the lungs via translocation, a process facilitated by increased gut and alveolo-capillary permeability.





Samiran M, Dusan H. Yale J Biol Med, 2018 Jun; 91(2): 143–149


How soap kills the coronavirus?


Soap breaks up the membrane of the virus and deactivates it. Wash often your hands for 20 seconds or more.


To protect yourself from COVID 19 you need to support your immune system.


To boost your immune system avoid certain foods:


- gluten - Gluten damages your gut. Dr Silverman says "Never been a better time to start in being gluten-free."

Many research studies have linked gluten to the condition known as intestinal permeability. Gluten directly impacts the intestinal lining through zonulin production. Zonulin is a protein that directly causes leaky gut. Leaky gut contributes to autoimmune disease.

- processed food

- sugar

- artificial sweeteners - artifitial sweeteners may change the balance of your gut bacteria and cause leaky gut.

- dairy - the highest allergic food, damages your gut, makes mucus

- detect and avoid food sensitivities

Proper diet leads to enhanced immunity. Poor diet causes impaired immunity.

Healthy diet to boost your immune system:


• Plant-based diet : Vegetables and fruits - provide many antioxidants, vitamins and minerals

• Wild fish - salmon, macrel, anchovy, sardines, herring

• Grass-fed meats

• Chicken soup and Bone broth

• High fiber - fiber is prebiotic which feeds good bacteria to keep your gut healthy

• Snack - organic dark chocolate

• Herbals - ginger, turmeric

• Oils – olive oil, avocado, macadamia nut

• Mushrooms - shiitake, reishi, , turkey tail, maitake, oyster, lion’s main

• Nuts, avocado, olive oil - Oleic acid (omega-9 fatty acid) from these foods stimulate SIRT1 – the defense enzyme

• Appropriate fluid intake - hydration is essential for our health.

Lifestyle changes to boost your immune system:


• Time-restrictive eating or intermittent fasting - fast for 12-16 hours

• Get sufficient sleep - 7-8 good quality hours of sleep - to improve your immune system.

Sleep deprivation increases insulin resistance, slows metabolism and increases inflammation.

• Humidity – keep humidity up at home to maintain airway health and mucus.

• Exercise plan - exercise improve sleep quality and sleep duration.

Immune support supplements:

• Vitamin C - Liposomal vitamin C is the best form.

• Vitamin D3 with K2 - 5000 - 10000 IU D3

• Zinc - zinc supplements (20 mg/d) are known to assist the immune system in fighting viral infections, especially by inhibiting viral replication.

• Mixed mushroom complex - have tremendous bioactive molecules that support immune function

• Probiotics

• Liposomal glutathione - glutathione is the master antioxidant

• Beta-glucans

• Omega-3 fatty acid

• Elderberry

Role of vitamin C in the body


Vitamin C is the main systemic extracellular antioxidant. When given at high doses, either orally (3-10 g/day) or IV (10-50 g/day, etc.), can function as an antioxidant to prevent toxicity from ROS (Reactive oxygen species) and viruses. When oxidized through donating an electron to reduce an ROS, it can be regenerated through a variety of mechanisms, including reducing enzymes and other antioxidants.

Vitamin C can support intracellular antioxidants such as GSH (glutathione) and catalase when the load of ROS is severe.

Vitamin C also empowers the immune system, promoting chemotaxis, growth and activity of some immune cells (macrophages, lymphocytes, natural killer cells) allowing the body to more effectively fight an infection.

Gropper SS, Smith JL (2013) Advanced Nutrition and Human Metabolism, 6th Ed. Wadsworth, Cengage Learning. ISBN-13 9781133104056.


Vitamin C has many other roles in which it functions as a specific co-factor for biochemical reactions, for example, in the synthesis of aggrecan and collagen in which it is necessary for the crosslinking of long fibers into a 3D matrix, in the absorption of iron, in the metabolism of many essential biochemicals including carnitine and neurotransmitters (e.g. norepinephrine, serotonin). Thus it is essential for recovery from damage caused by viral or bacterial infections.

In addition, when the body is under severe stress, for example, recovering from toxin exposure, surgery, or SARS, the level of vitamin C can be depleted so that it cannot perform its direct or indirect antioxidant functions or its many other specific co-factor roles in biochemical metabolism. This can in turn deplete the other antioxidants, e.g. glutathione and vitamin E, which can cause severe oxidative damage inside cells that normally they would prevent.

In high-dose intravenous vitamin C (IVC) therapy, vitamin C is thought to be a pro-oxidant in selective cell types, which allows it to kill specific cell types. This role may function in some types of cancer and also immune hyperinflammation.

Vitamin C supports intracellular antioxidants and is necessary as a specific co-factor in many critical biochemical reactions in many organs of the body.

Prevention of viral infections


Typically many individuals can tolerate 1000-3000 mg/day in divided oral doses, which can then maintain a relatively constant level of vitamin C in the bloodstream. Some organs (e.g. liver, brain, eyes, etc) actively transport vitamin C to maintain a higher level than provided by the blood. This state of a relatively high maintained level of vitamin C throughout the body is thought to lower the risk of viral infection by assisting the immune system in detecting and destroying foreign microbes such as viruses that attack the nasopharynx and lungs. In addition, oral doses of vitamin C can directly denature viruses.


Levy TE (2011) Primal Panacea. Medfox Pub. ISBN-13: 978-0983772804.

Liposomal vitamin C


Liposomal vitamin C is absorbed by a different mechanism in the gut. The liposomes containing vitamin C can bind directly to the gut cells to release their content of vitamin C which therefore does not require active transport. Thus the maximum level achievable with oral doses of liposomal vitamin C is higher than for regular vitamin C.

However, since the absorption mechanism for liposomal vitamin C differs from the active transport of regular vitamin C, both forms can be taken together to increase the level in the bloodstream (up to 400-600 μM), greater than either oral form alone.


Levy TE (2011) Primal Panacea. Medfox Pub. ISBN-13: 978-0983772804.

Orthomolecular Medicine News Service, Apr 3, 2020, Rationale for Vitamin C Treatment of COVID-19 and Other Viruses


Vitamin D


Vitamin D deficiency has been shown to be independently associated with increased risk of viral acute respiratory infection (ARI) in a number of observational studies, and meta-analysis of clinical trials of vitamin D supplementation for prevention of ARI has demonstrated protective effects.

Many studies have shown the effectiveness of vitamin D (2000-5000 IU/d) for preventing viral infections. Vitamin D has been shown to assist the body in preventing viral infections. What is important, the level of vitamin D in patients with flu is lower than healthy individuals. For those who do not supplementing vitamin D, the level of vitamin D is the lowest in the body in the winter and early spring time -- which is flu season. In a study of hospitalized older patients, those with with pneumonia more often had a severe vitamin D deficiency.


Orthomolecular Medicine News Service, Apr 3, 2020, Rationale for Vitamin C Treatment of COVID-19 and Other Viruses

The immunomodulatory actions of 1,25(OH)2D against respiratory viruses





Greiller CL, Martineau AR. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients. 2015;7(6):4240–4270. Published 2015 May 29


Vitamin D supplementation to prevent acute respiratory tract infections:


Vitamin D supplementation safe and protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient experienced the most benefit.


BMJ, Feb 15, 2017;356,i6583

Vitamin D/VDR and microbiome in intestine and other putative organs





Curr Opin Clin Nutr Metab Care. 2018 Nov; 21(6): 471–74


Sources of vitamin D: sunlight, food (fatty fish, like tuna, mackerel, and salmon; beef liver, egg yolks), suplementation.

Vitamin D regulates gut microbiome which helps maintain barriers and may inhibits inflammation in intestine and other areas.

Probiotics

Leo Galland MD:

"There is the thousand times more types of DNA from bacteria in your body than there is DNA that belongs to you. Bacteria growing in your gut affect every other aspect of your body. Your body does not exist whitout this bacteria. They specially affect the function of the brain. Over 90% of the substances, the chemicals circulating in your blood are not produced by your own cells. They are produced by the microbes most of whom are in your gut. "


The intestinal microbiota is an ecosystem containing tens of trillions of microorganisms including many species of known bacteria. Bacterial cells outnumber human cells in the body by approximately ten times with 10–100 trillion microbes living in the gastrointestinal tract alone. Probiotics are “live microorganisms which could possess a health benefit on the host when administered in appropriately adequate amounts”.

Hong Z, Chiajung Y, Zonglian J, et al. Synth Syst Biotechnol, June 2018;3(2):113-120. Published online 2018 March 12

The 12-week study with participants who had contracted a cold 4 times in the past year, indicates that the combination of probiotics (Lactobacillus paracasei, Lactobacillus casei 431® and Lactobacillus fermentum PCC®) could reduce the incidence of the upper respiratory infection by increasing the level of IFN-γ in the blood and sIgA in the gut.

Hong Z, Chiajung Y, Zonglian J, et al. Synth Syst Biotechnol, June 2018;3(2):113-120. Published online 2018 March 12

Spore probiotics


Spore-based probiotics are part of a group of derivatives of the microbe called bacillus. This genus has hundreds of subspecies, the most important of which is bacillus subtilis. Spore-based probiotics consist of the cell wall of bacillus spores.

These are soil-base microorganisms, formed from spores and found in dirt and vegetation.

Bacillus species are delivered as dormant spores. Endospores encapsulate beneficial bacteria are stable, high resistant to stomach acid and are more usable probiotics to the SI.

Bacillus subtilis protects microbes from harsh conditions, are shelf-stable, resist gastric hydrochloric acid. Helps adhere to intestinal epithelium and propagates bacteria in the large intestine.


Contrary to popular belief, the human body has the ability to produce its own vitamin C. This is done by a specific species of gut microbes — the bacillus. Bacillus converts sugar into vitamin C. It's also involved in producing vitamin K.


Spore probiotics is that they can more effectively help reestablish your gut microbiome since they're not being destroyed by antibiotics. Moreover, most acidophilus products have the drawback of not being able to survive the passage through your stomach acid if you take them on an empty stomach, which most people do.


The bacillus very effectively modulates cytokines — anti-inflammatory cytokines are upregulated while inflammatory cytokines are downregulated, thereby restoring balance between the two.

Cuentas, et al. Journal of Probiotics & Health, 2017;5:4 Fouad MFE, Namita R, Rohini DG, et al. Front. Microbiol. Aug 10, 2017 Kovács, ÁT. Bacillus subtilis. Trends in Microbiology, 2019;27(8):724-25

Beta glucans


Beta-glucans are naturally occurring polysaccharides. Various mushrooms, such as lingzhi, shiitake, chaga, and maitake, contain biologically active polysaccharides that mostly belong to group of beta-glucans. These substances increase host immune defense by activating complement system, enhancing macrophages and natural killer cell function. The induction of cellular responses by mushroom and other beta-glucans is likely to involve their specific interaction with several cell surface receptors, as complement receptor 3 (CR3; CD11b/CD18), lactosylceramide, selected scavenger receptors, and dectin-1 (betaGR). beta-Glucans also show anticarcinogenic activity.


Beta-glucans regulate the function of the innate immune system which is the first line of defense against viruses and bacteria. Beta-glucans help your white blood cells bind to and kill viruses and bacteria.


Akramiene D, Kondrotas A, et al. Medicina (Kaunas), 2007;43(8):597-606

Elderberry (Sambucus javanica Extracts).


Many evidences show the genus of Sambucus exerts a broad spectrum of medicinal potencies such as anticancer, antiviral, antibacterial, and antidiabetes. Bioactive compounds of Sambucus might alter several biological systems, including the immune system.

Elderberry contains several functional bioactive compounds: flavonoids and phenolic acids - phenolic compounds are potent modulators of the immune response – inflammation. Shown to reduce production: IL-16, IL-6 , TNF-ɑ and ROS.

Putra WE, Rifa’i M. Adv Pharm Bull, 2019 Oct;9(4):619-623

Tiralongo E, Wee SS, Lea RA. Nutrients, 2016 Mar 24;8(4):182



How to break down the shells that surround coronaviruses?



There are some research findings that there are glycoprotein shells covering the coronavirus SARS-CoV-2, which make it difficult to break the virus by the immune system.

Studies have also discovered that these Mannose-binding lectins spoil down the glycoprotein shells of the viruses noted above, including Ebola and SARS. A quantity of scientific evidences have shown that these mannose-binding lectins are successful in halting replication of the virus.


It means that certain plant medicines could be useful for novel coronavirus treatment. Our argument is based on research finding that coronavirus has viral envelope glycoproteins. Mannose-binding lectins have been shown to penetrate and break down the shells that surround this class of viruses – which includes coronavirus SARS-CoV-2. Mannose-binding lectins deficiency is also responsible for weakened immune system, which may affect pneumonia etc. For that reason, we can consider medicinal plants which have Mannosebinding lectins, to break the glycoproteins envelope of the coronavirus.

Review of possible treatment of coronavirus by three medicinal plants


1. Griffithsin red algae


According to Case Adams : Red algae Griffithsin has also verified to be antiviral towards HIV-1, HSV-2, HCV and the Ebola virus. These viruses have something in common: along with COVID-19, they all have glycoprotein shells around them.


Most of the commercial dietary supplements use of the Gigartina species of purple algae (such as Gigartina skottsbergii). This species has been tested towards HSV and HIV in laboratory testing, but not yet on SARS-CoV-2 to date.


2. Licorice root


Adams et al. have published evidence that licorice root can fight SARS and MERS CoV infections and is able to reduce SARS and MERS-CoV replication.


Licorice root supplements are only intended for short-term use. Consuming licorice daily for several weeks or longer can cause severe and potentially life-threatening side effects.


Researches show that licorice root consumption during pregnancy or breastfeeding leads to adverse neurological effects in children later in life. As such, it should not be consumed by children, pregnant women, or nursing mothers. Licorice should also be avoided in people with kidney or liver dysfunction.


Drug Interactions


Licorice can interact with a number of medications, either by reducing their efficacy (and making them less potent) or increasing their efficacy (and worsening their side effects).


These include:

  • Anti-arrhythmia drugs

  • Antihypertensive drugs

  • Anticoagulants ("blood thinners")

  • Estrogen-based contraceptives

  • Celebrex (celecoxib), and Voltaren (diclofenac)

  • Anticholesterol drugs like Lescol (fluvastatin)

  • Diuretics ("water pills") like Lasix (furosemide)

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) like Advil (ibuprofen)

3. Curcuma zedoaria


Another study by Tipthara et al. shows that Mannose-binding lectin was once isolated from rhizomes of the medicinal plant Curcuma zedoaria.


Case Adams. Can Herbal Medicines Fight Wuhan Coronavirus? The Journal of Plant Medicines, January 2020.

Dana Henry. Understanding Mannose-binding lectins deficiency. IG Living | October-November 2017

N. Banerjee & S. Mukhopadhyay. Viral glycoproteins: biological role and application in diagnosis. Virusdisease. 2016 Mar; 27(1): 1–11. url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758313/ [4] P. Tipthara et al. Mannose-binding lectins from curcuma zedoaria rosc. J. Plant Biology, April 2007, 50(2) : 167-173

R. Lobo et al., Curcuma zedoaria Rosc. (white turmeric): a review of its chemical, pharmacological and ethnomedicinal properties. J. Pharmacy and Pharmacology 2009, 61: 13–21

Atiqur Rahman et al. In vitro antioxidant potential of the essential oil and leaf extracts of Curcuma zedoaria Rosc. Journal of Applied Pharmaceutical Science Vol. 4 (02), pp. 107-111, February, 2014

Retno Murwanti et al. Effect of Curcuma zedoaria Rosc. ethanolic extract on the lung tumor growth on post initiation phase in female mice induced by Benzo(a)pyrene. Majalah Farmasi Indonesia, 15 (1), 7 - 12, 2004

Zacharias Wuragil. Viral curcumin bisa tangkal virus corona, ini kata penelitinya. 14 Februari 2020. url: https://tekno.tempo.co/read/1307643/viral-curcumin-bisatangkal-virus-corona-ini-kata-penelitinya/full&view=ok


Pro-inflammatory cytokines


Randy Cron, M.D., Ph.D., is a University of Alabama at Birmingham professor of pediatrics and medicine an expert in a dangerous immune reaction, called cytokine storm syndrome.

“Cytokines are inflammatory immunologic proteins that are there to fight off infections and ward off cancers,” said Cron, “But when they are out of control, they can make you very ill.”

A cytokine storm is the result of an immune system gone wild. The body’s own killer immune cells are often defective, what leads to increased production of inflammatory proteins (cytokines) that can cause organ failure and death.

Coronavirus-19 may cause serious damage to the respiratory tract, including the lung, called coronavirus disease (COVID-19). When virus infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6. The binding of Coronavirus-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1β which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1β which is a mediator of lung inflammation, fever and fibrosis.

Mediators of the cytokine storm and the associated phenotypes with infection outcome.



Jennifer RT, Marcus JK, Cameron PS, et al. Microbiol Mol Rev. 2012 Mar;76(1):16-32


The NLRP3 inflammasome is a multimeric protein complex that initiates an inflammatory form of cell death and triggers the release of proinflammatory cytokines IL-1β and IL-18. The NLRP3 inflammasome has been implicated in a multiple diseases, including Alzheimer's disease, type 2 diabetes, and some infectious diseases. It has been found that a variety of stimuli including danger-associated molecular patterns and pathogen-associated molecular patterns (PAMPs) can activate NLRP3 inflammasome.

Role of ion fluxes in NLRP3 inflammasome activation


Ion fluxes, including K + efflux, Ca 2+ mobilization, and Cl − efflux, have been proposed as crucial events in NLRP3 inflammasome activation.

Intracellular ions can function as signaling messengers, effectively linking distinct events upstream of NLRP3 activation.

Increasing evidence suggests that intracellular ions, such as K +, Ca 2+, and Cl −, have a significant role in NLRP3 inflammasome activation.


Yang, Y., Wang, H., Kouadir, M. et al. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis, 2019;10:128

LPS-induced Mitochondrial DNA contributes to NLRP3 inflammasome




Lipopolysaccharide (LPS) is the most abundant component within the cell wall of Gram-negative bacteria. It can stimulate the release of interleukin 8 (IL-8, CXCL8, CXC ligand 8) and other inflammatory cytokines in various cell types, leading to an acute inflammatory response towards pathogens.


A recent study in Nature by Zhong et al. shows that inflammasome priming drives new mitochondrial DNA synthesis, and proposes this to be a prerequisite for NLRP3 inflammasome signaling. When cells were primed with the TLR4 ligand lipopolysaccharide (LPS), NLRP3 activators also triggered an increase in oxidized mtDNA release into the cytosol. LPS stimulation was associated with a 2-3-fold increase in mtDNA copy number.


The release of lipopolysaccharides (LPS) in the intestine is a normal feature of metabolism. It is abnormal when the LPS leaks into the bloodstream and triggers inflammation downstream.


If you have an inflammatory diet and unhealthy gut, LPS can rise abnormally in the bloodstream causing metabolic endotoxemia (Leaky Gut).

Leaky gut fuels inflammation what increases risk for chronic disease.

Rebecca CC, Caroline LH, Kate S. Cell Research, Oct. 3, 2018. https://doi.org/10.1038/s41422-018-0093-8

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening diseases in critically ill patients. They are the manifestations of an inflammatory response of the lung to insults and are characterized by severe hypercapnia, hypoxemia, diffuse infiltration in the chest X-ray, and a reduction in pulmonary compliance.

Maximillian Ragaller and Torsten Richter, Acute lung injury and acute respiratory distress syndrome, J Emerg Trauma Shock. 2010 Jan-Mar;

How to modulate the cytokine storm:

• Ascorbic acid (vitamin C)

• Vitamin D

• Pro-resolving mediators

• Melatonin

• Curcumin

• PEA

• Stinging nettle

• Quercetin

Ascorbic acid - New York hospitals utilizing vitamin C


• COVID-19 intensive care patients immediately receiving 1500 mgs intravenously and re-administer exact amounts 3-4 times/day

“The patients who received vitamin C did significantly better than those who did not get vitamin C. It helps a tremendous amount, but it is not highlighted because it's not a sexy drug. “


Vitamin D deficiency contributes directly to ARDS


Vitamin D deficiency is common in people who develop ARDS (respiratory distress syndrome). This deficiency appears to contribute to development of this condition.

Vitamin D deficiency is a mechanistic driver of inflammation.

Vitamin D deficiency promotes defective resolution of infection and inflammation and treatment using this vitamin protects lung barrier integrity and improves cellular resolution of neutrophilic injury.

Approaches to correct vitamin D deficiency in patients at risk of respiratory distress syndrome should be developed.

Dancer RCA, Dhruv P, Sian L, et al. Thorax, 2015;70:617-24


Pro-resolving mediators (SPMs) - on of the best supplement to consider to modulate the cytokine storm


Pro-resolving mediators (SPMs) reductions may drive O3 -induced pulmonary inflammation.

The body creates pro-resolving mediators (SPMs) from fatty acids such as EPA and DHA omega-3s. Unfortunately fish oil is not completely converted to SPMs, so you may not get the optimal health benefit from taking a fish oil alone. Research indicates that SPMs and SPM precursors (such as 17-HDHA and 18-HEPE) work better for promoting a healthy post-inflammatory response to support whole-body health. SPMs promote the clearing of cellular debris and help maintain a healthy balance of cytokine compounds, and support healthy tissue rejuvenation.


Supplementation of precursors/SPMs decreased proinflammatory cytokine and chemokine expression.


B. Kilbury-Bas, S. W Reece, M. J Crouch, et al. SPM regulate ozone-induced pulmonary and systemic inflammation. Toxicol Sci. June 2018;163(2):466-477


Melatonin


Patients should consult a doctor before using melatonin.


Melatonin is a versatile molecule which is synthesized by the pineal gland and other organs, including gastrointestinal tract, thymus, retina, bone marrow, and by leukocytes. Melatonin is playing an important role in various functions of the body, including sleep and circadian rhythm regulation. Melatonin also shows immunoregulatory, free radical scavenger and antioxidant functions. Melatonin has also been found to be effective in fighting viral infections in a numerous experimental animal and in vitro studies. These data suggest a possible therapeutic potential of melatonin in human virus-induced disorders.

Silvestri, M., Rossi, G.A. Melatonin: its possible role in the management of viral infections-a brief review. Ital J Pediatr, 3 Oct 2013;39:61

Melatonin in experimental Respiratory Syncytial Virus infection



Silvestri, M., Rossi, G.A. Melatonin: its possible role in the management of viral infections-a brief review. Ital J Pediatr, 3 Oct 2013;39:61



R. Zhang, X. Wang, L. Ni, et al. COVID-19: Melatonin as a potential adjuvant treatment, Life Science, 23 Mar 2020 online

Curcumin suppression of cytokine release and cytokine storm


The terminal stage of Ebola and other viral diseases is often the onset of a cytokine storm which is the massive overproduction of cytokines by the immune system.


Curcumin blocks cytokine release, especially the key pro-inflammatory cytokines, interleukin-1, interleukin-6 and tumor necrosis factor-α. The suppression of cytokine release by curcumin correlates with clinical improvement in experimental models of disease conditions where a cytokine storm plays a significant role in mortality.


Intravenous curcumin formulations may allow to achieve the therapeutic blood levels of curcumin.

PETER P. SORDILLO and LAWRENCE HELSON, Curcumin Suppression of Cytokine Release and Cytokine Storm. A Potential Therapy for Patients with Ebola and Other Severe Viral Infections,  In vivo (Athens, Greece) 29(1):1-4 · January 201

Palmitoylethanolamide (PEA)


Palmitoylethanolamide is a natural body-own anti-inflammatory agent, effective and safe against influenza and common cold.


Palmitoylethanolamide (PEA) is a bioactive lipid that plays a key role in endocannabinoid system (ECS) responsible for promoting balanced systems, including the central nervous system and the peripheral nervous system.

Endocannabinoid system helps promote relaxation and healthy nerve function. PEA is being produced naturally in every cell of the body in biological response to inflammatory markers.

Palmitoylethanolamide (PEA) is a food component known for more than 50 years. PEA is synthesized and metabolized by different animal cell types and also present in plants. It exerts a multitude of physiological functions related to metabolic and cellular homeostasis. PEA was already identified in the 50s of the last century as a therapeutic substance with potent anti-inflammatory properties. The anti-inflammatory and other immune-modulating properties of PEA have been shown in many placebo-controlled double-blind clinical trials on influenza and common cold.


Research on PEA has been conducted for more than 50 years, and over 350 papers are referenced in PubMed describing the physiological properties of this endogenous modulator and its pharmacological and therapeutical profile.

Multiple mechanisms are associated with PEA: anti-inflammatory mechanism - inhibition of TNF-alpha & NFKb, immune support - PEA stabilizes mast cell and supports the endocannabinoid system.


PEA also works by attenuating the potentially deadly cytokine storm in influenza.

Int J Inflam.2013; 2013; 151028



Stinging nettle


Reduces inflammatory cytokine release and reduces inflammatory biomarkers like: TNF-a, TNF-a, IL-1 , IL-6, hs-CRP.


Johnston TA, Sohn J, Inman WD, et al. Phytomedicine, 2013 Jan 15;20(2):143-7




Quercetin (3,3′,4′,5,6-pentahydroxyflavone) is an antioxidant and a flavonol found in many fruits and vegetables. Quercetin also has known anti-inflammatory effects on lipopolysaccharide-induced macrophages. Quercetin had alleviating effects on viral inflammation based on inhibition of cytokines, nitric oxide, chemokines, and growth factors in dsRNA-induced macrophages.

Young-Jin Kim and Wansu Park, Anti-Inflammatory Effect of Quercetin on RAW 264.7 Mouse Macrophages Induced with Polyinosinic-Polycytidylic Acid, Molecules. 2016 Apr












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