Treatment of SARS-CoV-2-induced pneumonia with NAD+ and NMN

In Mouse models

Before I go any further, while this paper is a mouse model, they are just replicating a finding in humans, some doctors used high doses of Nicotinamide Mononucleotide (MNM) to rescue severe elderly patients who developed pneumonia during a Covid-19 infection and achieve unbelievable results.

Treatment of SARS-CoV-2-induced pneumonia with NAD+ and NMN in two mouse models

We therefore investigated the effect of treatment with NAD+ and its intermediate (NMN) and found that the pneumonia phenotypes, including excessive inflammatory cell infiltration, hemolysis, and embolization in SARS-CoV-2-infected lungs were significantly rescued. Cell death was suppressed substantially by NAD+ and NMN supplementation. More strikingly, NMN supplementation can protect 30% of aged mice infected with the lethal mouse-adapted SARS-CoV-2 from death. Mechanically, we found that NAD+ or NMN supplementation partially rescued the disturbed gene expression and metabolism caused by SARS-CoV-2 infection. Thus, our in vivo mouse study supports trials for treating COVID-19 patients by targeting the NAD+ pathway.

The abstract is pretty straightforward, by using NAD+, and especially NMN rescued the mice and corrected all the common effects the viral infection causes. The bold part is really important, because as I covered before, the (weird) cell death occurring in SARS-CoV-2 infections is one of the main drivers of the long-term low-grade inflammation MANY experiences, and most are unaware of.

Nicotinamide adenine dinucleotide (NAD+) and NADH are essential coenzymes for multiple cellular energy metabolism pathways, such as tricarboxylic acid (TCA) cycle and oxidative phosphorylation2. NAD+ also serves as a substrate for sirtuin deacetylases (SIRTs), cyclic ADP-ribose synthases (including CD38 and CD157), and poly- or mono-(ADP-ribose) polymerases (PARPs), and participate in many important biological processes, including cell survival, aging, inflammation, etc2,3,4. Besides, NAD+ can be phosphorylated to nicotinamide adenine dinucleotide phosphate (NADP+) by NAD+ kinase (NADK)5. Both NADP+ and its reduced form, NADPH, play critical roles in maintaining redox balance and biosynthesis of fatty acids and nucleic acids6,7. In mammalian cells, NAD+ is synthesized through the de novo pathway and the salvage pathway7.

One of the most striking disturbance in the sera of COVID-19 patients was the increase of metabolites related to de novo production of NAD+8. Whether and how NAD+ metabolism is disrupted in the lungs of COVID-19 patients is still not clear. NAD+ has been proposed as a selective inhibitor for SARS-CoV-2 main protease (Mpro) and multi-functional papain-like protease (PLpro)9,10. Recently, we found that NAD+ supplementation effectively alleviates cell death and inhibits microglia activation in Zika virus (ZIKV)-infected mouse brains11. Therefore, it is intriguing to explore whether NAD+ or its intermediates are protective from SARS-CoV-2 infection.

The first paragraph is important to understand if you want to dig deeper into human, and cell metabolism, in this case, the different paths and uses for NAD+. NAD and NADH are metabolized from different sources and are essential for life.

The second paragraph brings up something that is spoken only inside some circles, the striking uptake in metabolites (byproducts of your cells using “X” as nutrient/fuel) de novo, meaning new production. Why does SARS-CoV-2 affect NAD metabolism so badly?

From here.

Coronavirus replication results in expenditure of nicotinamide adenine dinucleotide (NAD+), the central catalyst of cellular metabolism, in the innate response to infection. Repletion of NAD+ levels has the potential to enhance antiviral responses.

From their earliest replication intermediates, coronaviruses elicit an attack on cellular NAD+. Cellular NAD+ becomes a battlefield in which the innate immune system and the virus struggle for the upper hand. Based on preclinical work demonstrating transcriptional upregulation of NAD+-consuming enzymes and particular NAD+ biosynthesis pathways2, early clinical data indicate that NAD+ repletion might constitute an antiviral treatment approach3 that could be generally useful against infectious agents that activate the interferon system. The caveat—as with all approaches targeted to inflammation

From here.

Compared with healthy individuals, NAD+ concentrations in tissues and organs are lower in older individuals and in patients with diseases associated with severe COVID-19 symptoms, including diabetes and cardiovascular disease.

Viral infections, including coronavirus infections, have been reported to further deplete cellular NAD+ stores.

From an old thread (the virus also does this btw, the reason I am putting it here).

John Paul @ThingsHiddenn

Ferroptosis causes mitochondrial dysfunction. This causes your body not being able to produce enough energy, too keep up with cleaning by antioxidants activity, there you can't replenish your nutrients, causing accumulation of inflammation and oxidative stress and ROS.

After infecting your cells, the virus (any virus really, but this one is a metabolic master), hijacks the cell machinery and your own metabolism for its nefarious purposes, depleting your body from nutrients, and enzymes it needs to fight the infection, further driving the initial shock to your system.

I have various posts covering the mitochondrial aspect of this virus.

Bio Briefing—SARS-CoV-2, senescence and mitochondrial dysfunction

SARS-CoV 2 - Mitochondria, natural immunity, avian flu

Reverse AIDS - Unofficial Part V

SARS-CoV-2 and mitochondrial Dysfunction

Mitochondrial dysfunction is known to activate hypoxia signaling under normoxic conditions. Decline in NAD+/NADH ratio, also known as pseudohypoxic state, plays an important role in mitochondria-nuclear communication in aging and diseases

I could go on for quite a long while on NAD+ deficiency, and the progression, or worsening of numerous diseases, safe to say this is one of the drivers of further inflammation, metabolic dysfunction, and impaired/dysfunctional immunity in the infected. Google NAD+ and Diabetes.

The point of sharing all these is so you understand that, from my perspective for the longest time, this is where all the dysfunction and damage starts very early, and sets off everything else.

Infection led to robust induction of chemokine and interleukin genes, including Il1b, Il6, Ccl2, Ccl3, Ccl4, Ccl7, Cxcl1, Cxcl2, Cxcl5, Cxcl9, and Cxcl10, and related receptor genes, including Ccr1, Ccr4, Ccr5, Ccr5, Ccr7, Cxcr2, Cxcr5, Il1r2, and Il1rn (Fig. 1c). Many significantly upregulated genes participated in neutrophil chemotaxis, including S100a8 and S100a9

In the JAK-STAT signaling pathway, Stat1, Stat2, and their target gene, Casp4, and inflammasome member, Nlrp3, were significantly induced. As the sensor component of inflammasome, NLRP3 plays a crucial role in innate immunity and inflammation in response to viral RNA26,27. CASP4 acts as essential effectors of NLRP3 inflammasome-dependent CASP1 activation and IL1B secretion. Both CASP1 and CASP4 can initiate and promote pyroptosis through GSDMD cleavage and activation

Here they did the usual of measuring specific genes to map the pathways used by the virus, and as usual, they corroborated previous findings from other researchers, I have covered different papers with similar findings and pathways. The second paragraph is very important because I covered recently the importance of NLRP3 and how it affects the inflammatory states you find in both Long Covid and a portion of the vaccinated.

These all have important roles in your immune response.

In addition, the downregulation of mitochondrial NAD+ transporter gene, Slc25a51, and a nucleoside transporter gene, Slc29a1 (Ent1), suggested that both the import of NAD+ from the cytoplasm into the mitochondria and the import of nicotinamide riboside (NR) into cells were hindered

Loss of SLC25A51 has been shown to lead to impaired mitochondrial functions34

Together with the evidence of significantly upregulated expression of Gzmb and cathepsin family genes, mitochondrial functions can be predicated to be affected in the infected lungs.

Here we have it, the mitochondrial function, and an ever-smaller angle to look into. This gene is very important, and dysfunction of the same can lead to severe consequences.

Altered expression of the Slc25* genes may serve as a marker of mitochondrial dysfunction in brain, which accompanies the development of many neurological and psychoemotional disorders.

The paper goes out to demonstrate that NAD+ and NMN both help recover everything described in the first paragraph.

NAD+ supplementation alleviates SARS-CoV-2-induced pneumonia

The above results indicate that NAD+ supplementation can protect the lung from inflammatory injury, including cell death, caused by SARS-Cov-2 infection in both aged and young mice.

NAD+ supplementation partially salvages the changes in gene expression caused by SARS-CoV-2 infection

This indicates that NAD+ treatment leads to reduced activation of macrophage. Moreover, the upregulation of Apaf1, the apoptosis protease activating factor, was also rescued very significantly by NAD+ treatment

In addition, severe inflammatory cell infiltration and cell death caused by SARS-CoV-2 infection might be rescued by NAD+ treatment through suppressing the expression of Cd200r3, Cd200r4, and Apaf1, and other related genes untested.

NMN supplementation partially rescues the disturbance of metabolism caused by SARS-CoV-2 infection

Following below, is the conclusion.

NADPH can provide the reducing equivalents for biosynthetic reactions and the oxidation-reduction, and allow the regeneration of glutathione (GSH)60. Lower levels of NADPH can weaken the red blood cell membrane and trigger hemolysis as the maintenance of red blood cells require large amounts of GSH.

Moreover, NMN supplementation significantly rescued many metabolites that were significantly reduced after SARS-CoV-2 infection, and helped to maintain the metabolic balance of SARS-CoV-2-infected lungs and protect the mice from death.

Taken together, based on our finding that NAD+ and NMN can alleviate the pathological damage of lungs and even death of SARS-CoV-2-infected mice and other groups’ studies of NAD+-boosting therapy for different diseases in humans2,4, trials for treating COVID-19 patients with NAD+, its intermediates or precursors should be considered.

NAD+, and its intermediates (nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have profound beneficial effects in anyone infected, regardless of severity, and especially for many of the vaccinated that experience lethargy, brain fog, any type of sluggishness, and the reason I recommended some weeks ago, and why Niacin is in my stack and I myself take it.

Niacin has a broader physiological effect, but it doesn’t become NAD+ to the amounts you would need in case of severe infection, so if you can buy either NR or NMN and stash it (or take it daily), NAD+ IV can do WONDERS for you, paired with glutathione or NAC IV, you will feel like a new person after 36 hours.

From a mechanistic point of view, and simplifying, without these byproducts of Vitamin B3, you can produce new glutathione, therefore you can’t fight the inflammation, the bioenergetic dysfunction (your bio-electricity in a crude way), and especially one of the biggest drivers of bad outcomes and everything else, ROS Reactive Oxygen Species, cell rust in a very simplistic description.

This piece is long as it is, with enough linked reading material to last the reader some time, but this post will be fairly important not to the next virus one about BA. 4, BA. 5, and South Africa news, but the next few months too.

For last, a breadcrumb, if you use the search tool and type IDO, you can find another clue.

Before I go any further, while this paper is a mouse model, they are just replicating a finding in humans, some doctors used high doses of Nicotinamide Mononucleotide (MNM) to rescue severe elderly patients who developed pneumonia during a Covid-19 infection.

You can buy me a coffee whenever you feel like it.

Deep appreciation for all the supporters!