When researching the literature for a natural therapeutic which may be useful in treating my proposed Smoldering Macrophage Syndrome, I found one that stands out. It seems almost custom-tailored to treat the disease. It is Andrographolide (Andro) and, it is known colloquially as the “King of Bitters” for the highly concentrated bitter taste of the Andrographis paniculata plant. It is also a staple of Traditional Chinese Medicine.

Andrographolide is a diterpene lactone compound extracted from Andrographis paniculata (Burm. F) Nees. Andrographis paniculata is also known as lanhelian, yijianxi, zhanshecao, kucao, kudancao, etc. Since this product originates in India, it is also known as Indian grass. This product is dry ground part of Jupiteraceae plant Andrographis paniculata (conus) may originate in South Asia. It is commonly cultivated in China such as in Fujian, Guangdong, Hainan, Guangxi, and Yunnan and also in Australia and was also introduced in Jiangsu and Shaanxi.

Andrographis paniculata is commonly used in traditional Chinese medicine. Its ability of relieving “snake venom, and internal injuries cough” was recorded in “Lingnan herbal medicine records.” “Quanzhou Materia Medica” described it as “heat-clearing and detoxifying, anti-inflammatory, detumescence and inhibition throat inflammation, dysentery and high fever.”

Andrographolide
https://pmc.ncbi.nlm.nih.gov/articles/PMC7122281/

Why it caught my attention is that it shows properties of being theoretically able to bind Spike Protein, prevent Foam Cell formation and quell cytokine release from activated macrophages. All three of these actions would ameliorate Smoldering Macrophage Syndrome.

First, let’s look at how Andro can potentially bind Spike, preventing it from entering cells.

In this study, we used docking and molecular dynamics simulations to understand the binding effect of andrographolide on the SARS-CoV-2 spike protein. During docking, a strong binding affinity was observed between the ligand and the target receptor protein. MD results demonstrated higher conformational fluctuations in the ligand-free protein compared to the bound form. Several residues in the active sites make conformational rearrangements for the S protein to interact with the ligand. While RBD experiences conformational transition to gain more stability upon binding with the ligand. This binding is strengthened via several non-covalent interactions that make the complex structure more stable with higher binding affinity. Overall findings of the study may shed some valuable insights concerning the development of potential therapeutics in the strategies for COVID-19 prevention.

Investigating the binding affinity of andrographolide against human SARS-CoV-2 spike receptor-binding domain through docking and molecular dynamics simulations
https://pubmed.ncbi.nlm.nih.gov/36764825/

Next, Andro has demonstrated abilities to prevent the formation of foam cells, which we have previously discussed as an action the Spike Protein is able to induce.

In conclusion, inhibition of CD36-mediated oxLDL uptake and induction of ABCA1- and ABCG1-dependent cholesterol efflux are two working mechanisms by which andrographolide inhibits macrophage foam cell formation, which suggests that andrographolide could be a potential candidate to prevent atherosclerosis.

Andrographolide Inhibits Oxidized LDL-Induced Cholesterol Accumulation and Foam Cell Formation in Macrophages
https://pubmed.ncbi.nlm.nih.gov/29298513/

The remaining property of Andro I would like to discuss today is its ability to reduce the expression of cytokines in macrophages. Specifically, the expression of cytokines the Spike is particularly fond of increasing.

Macrophages have remarkable heterogeneity and plasticity that allows them to efficiently respond to exogenous and endogenous signals by changing their functional phenotype11, 14. In this study, thioglycollate-elicited mouse peritoneal macrophage (F4/80+ population)26 have been used to investigate the immunomodulatory activities of andrographolide on the innate immune response in vitro. Our results indicated that andrographolide showed potent immunoregulatory properties in murine macrophages. Andrographolide reduced expression of inflammatory cytokines (TNF-α, IL-12, IL-1β, IL-18, and IL-6) in LPS activated macrophages, which is consistent with a previous report that andrographolide decreased TNF-α and IL-12 mRNA expression and cytokine production in murine peritoneal macrophages, although they did not detect IL-1β, IL-18, and IL-627.

Immunomodulatory activity of andrographolide on macrophage activation and specific antibody response
https://pmc.ncbi.nlm.nih.gov/articles/PMC4002847/

Now it is clear why andrographolide captured my attention: Because it appears to address both sides of the SMS equation.

If Smoldering Macrophage Syndrome is driven by persistent viral stimulation together with macrophages that remain trapped in a chronic inflammatory state, then the ideal therapeutic would do more than simply suppress inflammation. It would reduce the viral stimulus while helping restore normal macrophage biology.

Andrographolide appears to move in exactly those directions.

We examined studies which suggest antiviral activity against SARS-CoV-2. Other studies demonstrated that it limits pathological cytokine production by activated macrophages. Still others show that it prevents macrophages from transforming into foam cells by restoring cholesterol homeostasis.

Taken together, these actions make andrographolide one of the most intriguing natural compounds I have encountered in the context of my Smoldering Macrophage Syndrome hypothesis.

Thank you, as always, for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Also, a great thank you to the three new paid subscribers who have joined us since Monday. Please have a blessed weekend.

One-Time Donation
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

Most physicians are familiar with Macrophage Activation Syndrome (MAS)—a rare but devastating condition in which macrophages become explosively activated. Patients develop overwhelming inflammation, high fevers, liver dysfunction, dangerously elevated ferritin, and in severe cases, multiple organ failure. It is an immune system in hyperoverdrive.

Fortunately, very few people with COVID-19 or Long COVID develop MAS.

But what if the opposite problem is occurring?

What if macrophages aren’t exploding...

What if they’re simply refusing to stop?

A Different Kind of Macrophage Disease

Instead of producing an acute cytokine storm over days, imagine macrophages remaining partially activated for months—or even years.

Rather than causing dramatic organ failure, they quietly simmer, producing inflammatory cytokines, recruiting additional monocytes, stimulating fibrosis, remodeling blood vessels, and gradually impairing normal tissue repair.

I would like to propose this chronic state as a hypothesis:

Smoldering Macrophage Syndrome (SMS).

Unlike MAS, the fire never becomes an inferno.

Instead...

It simply never goes out.

What brought me to this hypothesis? The Spike Protein persists for a VERY LONG TIME in macrophages. And, as I have stated FROM THE BEGINNING. SPIKE IS SPIKE. The source matters not. It is evident from both infection – and vaccination.

We next assessed if Mac (Macrophages) were a viral source by quantifying spike protein in BALF CD45+CD64+ Mac using intracellular flow cytometry (Fig. 2b). Spike+ Mac was detected in 12 of 15 WCM and 8 of 10 OCM (Fig. 2c). Spike+ Mac frequency was 41% in WTMhi and OMhi, 25% in WTMlo and OMlo and 8.6% in WTMneg and OMneg (Fig. 2c). Spike+ Mac frequency correlated positively with viral RNA in total BALF cells and negatively with BALF Mac survival in culture (Fig. 2c).

To further assess SARS-CoV-2 replication in Mac, we examined double-stranded RNA and nonstructural protein 3 (NSP3) protein expression in BALF Mac over an 18-h culture period (Fig. 2d–f). At 8 h of culture, viral dsRNA and NSP3 proteins were increased in BALF Mac in all 8 WTMhi or OMhi, 5 of 9 WTMlo or OMlo and 3 of 8 WTMneg or OMneg (Fig. 2f and Extended Data Fig. 3a). Spike protein further increased over time in all WTMhi/OMhi and WTMlo/OMlo, but not in 4 of 8 OMneg macaques, suggesting SARS-CoV-2 had the ability to replicate in Mac. We also noticed an increased number of BALF Mac syncytia during the culture period, likely mediated by spike (Extended Data Fig. 3b), and filiform extensions in BALF Mac at 8 h of culture (Extended Data Fig. 3b), which facilitated connections between Macs (Fig. 2g). Confocal images showed NSP3 protein within some of these protrusions (Fig. 2d and Extended Data Fig. 3b), suggesting viral replication in BALF Mac through cell-to-cell propagation.

SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells
https://www.nature.com/articles/s41590-023-01661-4

Perhaps most damning:

Tissue-Level Molecular and Histopathologic Findings: Serial skin biopsies at 1,160, 1,249, and 1,364 days post-vaccination, all from truncal skin within areas of clinically active Grover’s disease, were nucleocapsid negative and demonstrated persistent spike protein deposition in endothelial cells and macrophages by automated immunohistochemistry with histopathologic correlation. Spike protein was also found in nerve fibers at 1,364 days. The 1,364-day skin biopsy contained multiple plasmid DNA elements, including spike gene sequences (S1-S3), ori1/ori2, and the SV40 enhancer, confirming durable retention of vaccine-derived DNA in somatic tissue by PCR amplification with agarose gel electrophoresis and Sanger sequencing.

Persistence of Vaccine mRNA, Plasmid DNA, Spike Protein, and Genomic Dysregulation Over 3.5 Years Post-COVID-19 mRNA Vaccination
https://esmed.org/MRA/mra/article/view/7631

However, in all of this I find hope and healing because macrophages are remarkably adaptable.

Unlike permanently damaged tissue, macrophages continuously change their phenotype in response to their environment. If the chronic stimulus (Spike) is removed—or if therapies can restore normal immune regulation—it may be possible to shift them away from a persistent inflammatory state and back toward one that supports tissue repair and resolution.

Perhaps Long COVID is not simply a disease of excessive inflammation.

Perhaps, in many patients, it is a disease of unresolved inflammation.

And if that is true...

Helping macrophages remember how to stop may become just as important as helping them fight.

Thank you for keeping me going. I appreciate all of your support and am always grateful to everyone in our community. Also, a great thank you to the generous donor who contributed over the weekend and to the two new paid subscribers who have joined us since Friday. Please have a blessed week.

One-Time Donation
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

When I discuss a pathological aspect of COVID and/or the Spike Protein, I feel compelled to search for answers. This week was no exception. After studying the literature, I found a natural supplement that actually addresses the issue of downregulated FcγRIIB: Resveratrol. Again, I find it fascinating how so many players in the field of natural COVID/Spike therapeutics play multiple roles. In this case, Resveratrol not only increases the expression of FcγRIIB, it also has been shown to be helpful in treating the very same autoimmune diseases most likely to occur post COVID/Spike Protein exposure.

Mice lacking FcγRIIB spontaneously develop lupus-like autoimmune disease with high autoantibody production and immune-complex injury. It is a reminder that the immune system depends just as much on inhibition as it does on activation. This finding was part of the foundation for Monday’s hypothesis that Spike molecular mimicry with FcγRIIB may be inducing a similar lack of FcγRIIB in humans.

FcγRIIB is an inhibitory receptor expressed throughout B cell development. Diminished expression or function is associated with lupus in mice and humans, in particular through an effect on autoantibody production and plasma cell (PC) differentiation. Here, we analyzed the effect of B cell–intrinsic FcγRIIB expression on B cell activation and PC differentiation. Loss of FcγRIIB on B cells in Fcgr2b–conditional KO (Fcgr2b-cKO) mice led to a spontaneous increase in autoantibody titers.

FcγRIIB regulates autoantibody responses by limiting marginal zone B cell activation
https://www.jci.org/articles/view/157250

As I stated earlier, this is where Resveratrol may have added therapeutic value in treating/preventing autoimmune complications from COVID/Spike Protein. Resveratrol may compensate for FcγRIIB’s diminished expression in the context of COVID/Spike Protein by increasing its expression.

Resveratrol, an anti-inflammatory agent, can inhibit pro-inflammatory mediators by activating Sirt1, which is a class III histone deacetylase. However, whether resveratrol can regulate inhibitory or anti-inflammatory molecules has been less studied. FcγRIIB, a receptor for IgG, is an essential inhibitory receptor of B cells for blocking B-cell receptor-mediated activation and for directly inducing apoptosis of B cells. Because mice deficient in either Sirt1 or FcγRIIB develop lupus-like diseases, we investigated whether resveratrol can alleviate lupus through FcγRIIB. We found that resveratrol enhanced the expression of FcγRIIB in B cells, resulting in a marked depletion of plasma cells in the spleen and notably in the bone marrow, thereby decreasing serum autoantibody titers in MRL/lpr mice. The upregulation of FcγRIIB by resveratrol involved an increase of Sirt1 protein and deacetylation of p65 NF-κB (K310).

Upregulation of FcγRIIB by resveratrol via NF-κB activation reduces B-cell numbers and ameliorates lupus
https://pmc.ncbi.nlm.nih.gov/articles/PMC5628277/

If we look at the autoimmune diseases most likely to occur post COVID/Spike Protein exposure, Resveratrol has shown its worth in treating those diseases.

SLE (Lupus)

With regard to lupus cardiovascular disease, in vivo studies revealed that RSV (Resveratrol) has a therapeutic effect on atherosclerotic cardiovascular disease in SLE due to its antioxidant properties (101,106). These results were confirmed in vivo in a double-knockout ApoE−/− FAS−/− SLE mouse model (106). The authors found that mice in the RSV-treated group had fewer atherosclerotic plaques than those in the untreated group (not statistically significant), and that 43% of the RSV-treated animals had no plaques (106). In a different study, the authors evaluated the progression of aortic atherosclerosis in mice with SLE associated atherosclerosis after 10 weeks of oral treatment with RSV 0.3–0.4 mg/day in the treatment group (101). RSV was found to counteract the effect of SLE on atherosclerosis by preventing lipid excess by increasing cholesterol efflux (101). These findings suggest that RSV therapy may provide a novel approach to reduce the atherosclerotic cardiovascular effects of SLE.

In addition, a recent study also found that in lupus mice treated with water containing 0.01% RSV, RSV increased the level of SIRT1 in the hippocampus and decreased the level of vascular endothelial growth factor and C-X3-C motif chemokine ligand 1 (CX3CL1) by activating adenosine A2A receptors, but it was not statistically significant. It also showed a tendency to improve motor coordination in arteriosclerosis-prone lupus mice (107). This finding indicated that RSV may be a potential therapeutic candidate for the regulation of cognitive dysfunction in neuropsychiatric lupus, especially in motor disorders.

Potential of resveratrol in the treatment of systemic lupus erythematosus (Review)
https://www.spandidos-publications.com/mmr/30/4/182

RA (Rheumatoid Arthritis)

Resveratrol, a natural phytohormone, has attracted much attention in recent years owing to its therapeutic effects on RA. It was found that resveratrol can inhibit mitogen-activated protein kinase (MAPK), nuclear factor κB (NF-κB), and other cellular signaling pathways, thereby inhibiting the production and release of interleukins, proinflammatory cytokines, and matrix metalloenzymes. In addition, resveratrol can induce the apoptosis of MH7A, FLS, and inflammatory cells in RA, regulate macrophage differentiation and function, and protect the normal redox kinetics of mitochondria. Furthermore, resveratrol can effectively relieve synovial inflammation, proliferation, and cartilage destruction in RA. In particular, resveratrol has been shown to reduce RA-related complications, such as periodontitis, AF, and interstitial pneumonia.

The role of resveratrol on rheumatoid arthritis: From bench to bedside
https://pmc.ncbi.nlm.nih.gov/articles/PMC9465647/

Diabetes

Lee et al. (2011) conducted an investigation to assess the potential of resveratrol in preventing and treating Type 1 Diabetes (T1DM). In their study, resveratrol was administered both orally (at a dose of 250 mg/kg) and via subcutaneous injection (at a dose of 25 mg/kg) to non-obese diabetic mice. The results were striking, as they revealed not only prevention of T1DM but also the reversal of more advanced stages of insulitis within the islets of Langerhans.

Unveiling resveratrol’s potential: Navigating the landscape of autoimmune diseases
https://www.sciencedirect.com/science/article/pii/S2097382924000167

Resveratrol is eagerly raising its hand to answer the call for COVID/Spike Protein therapeutics. It is my hope that clinicians and researchers with labs will embark on studies using Resveratrol in treating/preventing the autoimmune conditions most commonly seen after COVID/Spike Protein exposure. Of course, please remember that this is a work of medical research and not medical advice. Always consult with your primary care provider before using any supplement or medication.

Thank you for keeping me going. I appreciate all of your support and am always grateful to everyone in our community. Please have a blessed weekend.

One-Time Donation
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

A review was just published on July 10^th which discusses the incidence and types of autoimmune disease post COVID infection. What I found interesting (see above table) is that connective tissue disorders were at the top of the list.

Taken together, the evidence supports a clinically meaningful but provisional conclusion: SARS-CoV-2 infection is associated with an increased risk of incident autoimmune disease, the association is strongest for connective tissue, vasculitic, and antibody-mediated disorders, and it is modulated by infection severity, time since infection, and possibly vaccination. The implications for practice are that clinicians should remain alert to new autoimmune presentations in the post-acute period after COVID-19, particularly in patients who experienced severe acute illness, while recognising that the absolute risk for any individual condition remains low. The implications for research are that future studies should prioritise active outcome ascertainment with serological and clinical confirmation, incorporate infection comparators to control for surveillance effects, extend follow-up to distinguish transient from durable risk, and stratify by variant and vaccination status. Only with such designs can the field move from demonstrating association toward establishing causation and quantifying attributable risk with confidence. In parallel, the identification of serological or transcriptomic biomarkers capable of flagging individuals at elevated risk would allow post-infection surveillance to be targeted rather than applied indiscriminately, improving both its diagnostic yield and its cost-effectiveness.

Autoimmune Manifestations Following COVID-19 Infection: A Systematic Review
https://www.cureus.com/articles/508282-autoimmune-manifestations-following-covid-19-infection-a-systematic-review#!/

Dysfunction of a receptor called FcγRIIB is directly tied to the development of connective tissue autoimmune disorders. Including Lupus.

Abnormalities in B cell function and in the clearance and inflammatory response to immune complexes are characteristic features of SLE. As FcγRIIB is a key regulator of B cells, and low affinity FcγRs are central to the response to immune complexes, FcγRIIB might be expected to be involved in the pathogenesis of SLE and perhaps other autoimmune diseases.

The most direct evidence for the role of FcγRIIB in SLE comes from studies involving genetically modified mice1. FcγRIIB deficiency renders normally resistant strains of mice susceptible to several antibody- or immune complex-dependent models of autoimmunity, including immune complex-mediated alevolitis51 and glomerular basement membrane-specific antibody-mediated nephritis67,105.

FcγRIIB-deficient mice backcrossed to a C57BL/6 background spontaneously develop hypergamma-globulinaemia, autoantibodies and an immune complex-mediated disease resembling SLE106; this does not occur on mice backcrossed to a BAlB/c background, indicating the importance of strain-specific epistatic effects on autoimmune susceptibility. The restoration of FcγRIIB expression levels on bone marrow cells of (NZB × NZW) F1 mice (a mouse model of spontaneous SLE) using an FcγRIIB-expressing retrovirus can prevent autoimmunity107, and modest transgenic overexpression of FcγRIIB on B cells markedly reduces the development of SLE in MRL-lpr mice42. Thus, studies in genetically modified mice implicate FcγRIIB in the pathogenesis of auto immunity and the maintenance of B cell tolerance. Some uncertainty remains, however, owing to the possibility that neighbouring genes might be influencing the phenotype of FcγRIIB-deficient mice (see BOX 1).

FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications
https://pmc.ncbi.nlm.nih.gov/articles/PMC4148599/

And Rheumatoid Arthritis.

Collagen-induced arthritis (CIA) is a B cell-dependent mouse model of inflammatory arthritis that shares some features with rheumatoid arthritis. FcγRIIB deficiency increases both collagen-specific IgG titres and disease severity in CIA52. Consistent with this, FcγRIIB B cell transgenic mice show a reduction in disease severity and in collagen-specific IgG titres; however, this effect was not observed in FcγRIIB macrophage transgenic mice42. In addition to influencing CIA through it effects on antibody production, FcγRIIB may also limit cartilage destruction by inhibiting the production of matrix metalloproteinases115.

FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications
https://pmc.ncbi.nlm.nih.gov/articles/PMC4148599/

Why is this so important? FcγRIIB is one of the immune system’s most important inhibitory receptors. Unlike activating Fc gamma receptors, FcγRIIB functions as a brake. When immune complexes bind to both the B-cell receptor and FcγRIIB, intracellular signaling through its ITIM motif recruits phosphatases such as SHIP1, suppressing further B-cell activation and antibody production.

In simple terms, FcγRIIB helps tell the immune system:

“You’ve done enough. Stop.”

Without that inhibitory signal, B cells remain more easily activated, plasma cells continue producing antibodies, and immune tolerance becomes increasingly difficult to maintain.

FcγRIIB is the only inhibitory Fc receptor. It controls many aspects of immune and inflammatory responses, and variation in the gene encoding this protein has long been associated with susceptibility to autoimmune disease, particularly systemic lupus erythematosus (SLE). FcγRIIB is also involved in the complex regulation of defence against infection.

FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications
https://pmc.ncbi.nlm.nih.gov/articles/PMC4148599/

To bring this all together, one particularly intriguing finding comes from a computational structural analysis published in Viruses. Using AlphaFold2-derived structural comparisons, the investigators identified a Spike-derived epitope (TGIAV) with striking structural similarity to an exposed region of FcγRIIB. The similarity (RMSD 0.17 Å) led the authors to nominate FcγRIIB as a potential target of Spike-induced molecular mimicry.

Human AF-3D-mimics for SARS-CoV-2 Spike.

• Motif- TGIAV

• Protein - Low affinity immunoglobulin gamma Fc region receptor II-b

• RMSD (Å) - 0.17

• Z-Score - −1.63

• EpiScore - 29.41

• AlphaFold2 ID - AF-P31995-F1-model_v1_A

Potential Autoimmunity Resulting from Molecular Mimicry between SARS-CoV-2 Spike and Human Proteins
https://www.mdpi.com/1999-4915/14/7/1415

This hypothesis needs to be thoroughly tested, yet it provides a biologically plausible mechanism that could contribute to the increased incidence of connective tissue and other antibody-mediated autoimmune diseases reported after SARS-CoV-2 infection/Spike Protein exposure. Determining whether anti-Spike antibodies actually bind and impair FcγRIIB should now be an important experimental priority.

As I always state, thank you for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Great thanks to the two new Paid Subscribers who have joined since Friday. Please have a blessed week.

One-Time Donation
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

If my hypothesis in Monday’s post is correct that persistent Spike Protein contributes to an Obliterative Foam-Cell Arteriopathy (OFCA) within the microvasculature, then an obvious question follows:

Can we slow or even prevent foam-cell formation?

This is an important question as foam cells are involved in COVID pathology independently of my proposed mechanism.

COVID-19 and long COVID are characterized by a dysregulated immune response. However, the role of macrophages during viral infection is poorly defined. Here we demonstrate that SARS-CoV-2 infection results in increased macrophage numbers and extensive formation of enlarged lipid-laden macrophages or foam cells using humanized mice, rhesus macaques and post-mortem human lung tissue.

SARS-CoV-2 infection induces pro-fibrotic and pro-thrombotic foam cell formation
https://www.nature.com/articles/s41564-025-02090-9

While no nutraceutical has been proven to reverse this proposed process in Long COVID, three natural compounds repeatedly emerge in the scientific literature for their ability to target the very biology that creates foam cells. And they should sound very familiar to us: berberine, resveratrol and curcumin.

As an ensemble, they attack the foam-cell problem from complementary directions.

Let’s start with berberine.

Berberine reduces the amount of oxidized LDL entering macrophages while simultaneously increasing cholesterol efflux through the LXRα–ABCA1 pathway. In simple terms, it helps macrophages remove cholesterol rather than becoming bloated with it. Multiple studies have demonstrated that berberine suppresses foam-cell formation in experimental models by enhancing reverse cholesterol transport and reducing lipid accumulation.

Berberine, a botanical alkaloid purified from Cortidis rhizoma, has effects in cardiovascular diseases, yet the mechanism is not fully understood. Foam cells play a critical role in the progression of atherosclerosis. This study aimed to investigate the effect of berberine on the formation of foam cells by macrophages and the underlying mechanism. Treatment with berberine markedly suppressed oxidized low-density lipoprotein (oxLDL)-mediated lipid accumulation, which was due to an increase in cholesterol efflux. Berberine enhanced the mRNA and protein expression of ATP-binding membrane cassette transport protein A1 (ABCA1) but did not alter the protein level of ABCG1 or other scavenger receptors. Additionally, functional inhibition of ABCA1 with a pharmacological inhibitor or neutralizing antibody abrogated the effects of berberine on cholesterol efflux and lipid accumulation. Moreover, berberine induced the nuclear translocation and activation of liver X receptor α (LXRα) but not its protein expression. Knockdown of LXRα mRNA expression by small interfering RNA abolished the berberine-mediated protective effects on ABCA1 protein expression and oxLDL-induced lipid accumulation in macrophages. These data suggest that berberine abrogates the formation of foam cells by macrophages by enhancing LXRα-ABCA1-dependent cholesterol efflux.

Anti-atherogenic effect of berberine on LXRα-ABCA1-dependent cholesterol efflux in macrophages
https://onlinelibrary.wiley.com/doi/full/10.1002/jcb.22667

Resveratrol, the polyphenol found in grapes and red wine, offers a second angle. It activates SIRT1 and promotes expression of ABCA1 and ABCG1, the transport proteins responsible for exporting cholesterol from macrophages. It also reduces expression of scavenger receptors such as CD36 and SR-A, making macrophages less likely to ingest oxidized LDL in the first place. Animal studies have shown significant reductions in atherosclerotic plaque burden alongside reduced foam-cell formation.

Resveratrol is a type of flavonoids (3,5,40-trihydroxystilbene) found in red wine, berries, and peanuts. This phytochemical can suppress foam cell formation and inhibit atherosclerosis both in vitro and in vivo. Among existing randomized controlled trials, 2000 mg/d is the maximum resveratrol dose with no observed severe adverse effects [79]. A study observed that 10 weeks of resveratrol treatment reduced atherosclerotic lesion size by 38 % and also decreased cholesterol levels in the aortas of apoE-/- mice. Additionally, western blot analysis demonstrated that resveratrol could reduce the expression of scavenger receptors (CD36 and SR-A) and upregulate the expression of cholesterol transporter (ABCA1 and ABCG1). These results indicated that resveratrol could inhibit lipid accumulation in macrophages by modulating cholesterol transporters in apoE-/- mice [80]. In another study, atherosclerotic plaques reduction was observed in both the branchiocephalic arteries and aortic sinus in apoE-/- mice fed a high-fat diet [50]. Resveratrol supplementation inhibited the progression of atherosclerosis. Furthermore, resveratrol suppressed oleate-induced TC and CE accumulation in macrophages by activating PPAR signaling [50].

Phytochemicals alter foam cell formation and macrophage cholesterol efflux
https://www.sciencedirect.com/science/article/pii/S3051307326000027

To complete our trifecta. Curcumin, the principal polyphenol in turmeric, approaches the problem from yet another angle. It suppresses NF-κB, inhibits LOX-1 and CD36 signaling, decreases oxidized LDL uptake and shifts macrophages toward a less inflammatory phenotype. Since chronic inflammation perpetuates foam-cell survival, curcumin may help interrupt that cycle before it becomes self-sustaining.

Treatment with curcumin markedly ameliorated oxidized low-density lipoprotein (oxLDL)-induced cholesterol accumulation in macrophages, which was due to decreased oxLDL uptake and increased cholesterol efflux. In addition, curcumin decreased the protein expression of scavenger receptor class A (SR-A) but increased that of ATP-binding cassette transporter (ABC) A1 and had no effect on the protein expression of CD36, class B receptor type I (SR-BI), or ATP-binding cassette transporter G1 (ABCG1). The downregulation of SR-A by curcumin was via ubiquitin–proteasome–calpain-mediated proteolysis. Furthermore, the curcumin-induced upregulation of ABCA1 was mainly through calmodulin-liver X receptor α (LXRα)-dependent transcriptional regulation. Curcumin administration modulated the expression of SR-A, ABCA1, ABCG1, and SR-BI in aortas and retarded atherosclerosis in apoE−/− mice.

Conclusion

Our findings suggest that inhibition of SR-A-mediated oxLDL uptake and promotion of ABCA1-dependent cholesterol efflux are two crucial events in suppression of cholesterol accumulation by curcumin in the transformation of macrophage foam cells.

Molecular mechanism of curcumin on the suppression of cholesterol accumulation in macrophage foam cells and atherosclerosis
https://onlinelibrary.wiley.com/doi/10.1002/mnfr.201100735

Taken together, these three compounds target nearly every major step in foam-cell biology:

• Reduce uptake of oxidized LDL

• Increase cholesterol efflux through ABCA1

• Decrease oxidative stress

• Suppress chronic inflammatory signaling

• Improve endothelial function

• Support healthier macrophage behavior

This is precisely why they caught my attention. Sometimes the best therapies are those that quietly interrupt pathology before irreversible damage occurs. As I always state, thank you for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Please have a blessed weekend.

One-Time Donation
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

OFCA is characterized by the accumulation of lipid-laden macrophages in the intima causing narrowing. A thin adventitial cuff of fibrous tissue and mononuclear cell infiltration is present. HE staining, ×200. HE: Hematoxylin–Eosin; OFCA: Obliterative foam-cell arteriopathy

Recently, I came across a little-known vascular pathology called Obliterative Foam-Cell Arteriopathy (OFCA). The more I read, the more I wondered whether it might provide a framework for understanding persistent Spike Protein-induced vascular disease, especially since it is at the crossroads of so many Spike Protein-related pathologies.

OFCA is morphologically defined as a localized (single-organ) form of vasculopathy limited to small-sized or medium-sized arteries characterized by accumulation of lipid-laden macrophages in the intima causing narrowing or complete obstruction. OFCA is mainly a disease of the arterial intima. We propose to group a series of previously described entities, such as ionizing radiation arteriopathy, acute atherosis (foam-cell decidual arteriopathy), transplant arteriopathy of solid organ allografts, and intratumoral-associated foam-cell arteriopathy that constitute different manifestations of the same basic morphological process identified as OFCA. The basic mechanism of development of this arteriopathy is endothelial activation and dysfunction (local arterial endotheliopathy).

Obliterative foam-cell arteriopathy. A unifying concept embracing several entities previously described as radiation, decidual, transplant, and intratumoral-associated arteriopathy
https://pmc.ncbi.nlm.nih.gov/articles/PMC10863698/

Look at the last sentence in the above quote. Aren’t “endothelial activation and dysfunction” the quintessence of SPED (Spike Protein Endothelial Disease)?

The elements exist. The Spike activates the endothelium and causes endothelial dysfunction.

Although the use of a noninfectious pseudovirus is a limitation to this study, our data reveals that S protein alone can damage endothelium, manifested by impaired mitochondrial function and eNOS activity but increased glycolysis. It appears that S protein in ECs increases redox stress which may lead to AMPK deactivation, MDM2 upregulation, and ultimately ACE2 destabilization.4 Although these findings need to be confirmed with the SARS-CoV-2 virus in the future study, it seems paradoxical that ACE2 reduction by S protein would decrease the virus infectivity, thereby protecting endothelium. However, a dysregulated renin-angiotensin system due to ACE2 reduction may exacerbate endothelial dysfunction, leading to endotheliitis.

SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.121.318902

And the Spike Protein activates macrophages.

Results

We found TLR4 to be the most abundantly upregulated TLR in human lung tissue irrespective of the underlying pathology. Accordingly, bronchoalveolar lavage fluid cells from patients with severe COVID-19 showed an NF-κB-pathway dominated immune response, whereas they were mostly defined by type I interferon signalling in moderate COVID-19. Mechanistically, we found the Spike ectodomain, but not receptor binding domain monomer to induce TLR4-dependent inflammation in human macrophages. By using pharmacological inhibitors as well as CRISPR/Cas9 deleted macrophages, we identify SARS-CoV-2 to engage canonical TLR4-MyD88 signalling. Importantly, we demonstrate that TLR4 blockage prevents exaggerated inflammatory responses in human macrophages infected with different SARS-CoV-2 variants, including immune escape variants B.1.1.7.-E484K and B.1.1.529 (omicron).

Conclusion

Our study critically extends the current knowledge on TLR-mediated hyperinflammatory responses to SARS-CoV-2 in human macrophages, paving the way for novel approaches to tackle severe COVID-19.

SARS-CoV-2 activates the TLR4/MyD88 pathway in human macrophages: A possible correlation with strong pro-inflammatory responses in severe COVID-19
https://pmc.ncbi.nlm.nih.gov/articles/PMC10686889/

One finding especially caught my attention that really brought this hypothesis into focus. Investigators discovered that SARS-CoV-2 does not merely activate macrophages—it preferentially infects lipid-laden foam cells within human coronary plaques. Even more striking, infected foam cells produced a robust pro-atherogenic inflammatory response.

Here we show, in coronary autopsy specimens from patients with COVID-19, that infiltrating macrophages were infected by SARS-CoV-2. Lipid-laden macrophages (foam cells), a hallmark of atherosclerosis at all stages of the disease10, were more susceptible to SARS-CoV-2 infection than other macrophages, and this was dependent on the receptor neuropilin-1 (NRP-1). SARS-CoV-2 induced a strong pro-atherogenic inflammatory response in both macrophages and foam cells, which was largely recapitulated in an ex vivo SARS-CoV-2 infection of human vascular explants. This response may contribute to the ischemic cardiovascular complications in patients with COVID-19.

SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels
https://www.nature.com/articles/s44161-023-00336-5

If foam cells themselves can harbor persistent viral material, they may function not simply as markers of vascular injury but as chronic inflammatory reservoirs capable of sustaining endothelial dysfunction long after the acute infection has resolved.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection. Here we used a model of viral infection in macaques to address whether SARS-CoV-2 persists in the body and which mechanisms regulate its persistence. Replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages beyond 6 months postinfection.

SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells
https://www.nature.com/articles/s41590-023-01661-4

Putting all this together, here is what I propose may be occurring:

Persistent Spike Protein
↓
Chronic Endothelial Injury
↓
Oxidative Stress
↓
Oxidized LDL
↓
Foam Cell Formation
↓
IL-6 • ROS • TGF-β
↓
Further Endothelial Injury
↓
Progressive Luminal Narrowing
↓
Microvascular Rarefaction
↓
Chronic Tissue Ischemia

Of course, this remains a hypothesis, but one that is experimentally testable—and, if correct, could help explain the persistent vascular dysfunction observed in Long COVID and what may be occurring to some degree to all exposed to the Spike Protein. Thank you for keeping me going. I appreciate all of your support and am grateful for everyone in our community. Please have a blessed week.

One-Time Donation
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

What’s old is new again.

Danshen, which is also known as Red Sage, is a member of the mint family that has been serving the health of mankind for millennia.

Salvia miltiorrhiza Bunge (S. miltiorrhiza), also known as Danshen (in Chinese) or Dansam (in Korean), is also commonly known as Chinese sage or red sage (Jung, Kim, Moon, Lee, & Kim, 2020). S. miltiorrhiza (SM) Bunge is a perennial plant that belongs to the genus Salvia of the mint family Lamiaceae (Jia et al., 2019). According to Koreans’ original text of the Donguibogam (written in the 17th century), Dansam effectively removes blood stasis and enriches the blood (Jun, 1980). Similarly, in Chinese medicine theory, Danshen helps with blood circulation, clears menstruation, and relieves pain and swelling (Zhou, Zuo, & Chow, 2005). The dried roots of these plants have been used as folk or traditional medicine in Japan, Korea and China for hundreds of years to treat a variety of diseases, such as cancers (Yang, Ju, Jeon, Han, & Shin, 2010), cardiovascular diseases (Sun et al., 2005), liver diseases (Lee et al., 2006), and nervous system diseases (Zhou, Li, Xu, & Chen, 2011). Danshen tea is widely used as a healthy food to prevent coronary heart disease (Shi, Huang, Deng, Wang, & Kai, 2019). There are several types of Danshen preparations for clinical application, including injections, capsules, tablets, granules, medicinal granules and dripping pills (Liu et al., 2015). The Compound Danshen Dripping Pill (CDDP) and Fufang Danshen tablets are the two most famous products (Fang et al., 2014, He et al., 2015, Zhang and Wang, 2006). Notably, Dantonic® (T89, also known as Compound Danshen Dripping Pills) is the first TCM that has completed Phase III clinical trials in the United States.

Review of Danshen: From its metabolism to possible mechanisms of its biological activities
https://www.sciencedirect.com/science/article/pii/S1756464621002620

Danshen, the root and rhizome of Salvia miltiorrhiza Bunge, was one of the earliest and also the most commonly used herbal drug in practice of TCM. The earliest record of Danshen appears to come from the (Shen Nong Materia Medica, A.D. 102–200) E. Han Dynasty. According to the theory of TCM, Danshen is bitter in taste and slightly cold in property, and enters the heart and pericardium meridians. The traditional curative functions are to invigorate blood, remove stagnation, cool blood, reduce carbuncles and clear heat in the heart and soothe irritability (Liu et al., 2000).

Investigation of Danshen and related medicinal plants in China
https://www.sciencedirect.com/science/article/abs/pii/S0378874108005059

What makes this ancient therapeutic new for us, is how it has shown the ability to be effective against the Spike Protein on a number of fronts. First, experimental studies suggest its salvianolic acids can inhibit Spike-mediated viral entry by binding both the Spike receptor-binding domain and ACE2. Access Denied!

Studies have reported that the traditional Chinese medicine Salvia miltiorrhiza possesses remarkable antiviral properties; however, the anti‐coronaviral activity of its main components, salvianolic acid A (SAA), salvianolic acid B (SAB), and salvianolic acid C (SAC) is still debated. In this study, we used Cell Counting Kit‐8 staining and flow cytometry to evaluate the toxicity of SAA, SAB, and SAC on ACE2 (angiotensin‐converting enzyme 2) high‐expressing HEK293T cells (ACE2h cells). We found that SAA, SAB, and SAC had a minor effect on the viability of ACE2h cells at concentrations below 100 μM. We further evaluated the binding capacity of SAA, SAB, and SAC to ACE2 and the spike protein of 2019‐nCoV using molecular docking and surface plasmon resonance. They could bind to the receptor‐binding domain (RBD) of the 2019‐nCoV with a binding constant (K D) of (3.82 ± 0.43) e−6 M, (5.15 ± 0.64)e−7 M, and (2.19 ± 0.14)e‐6 M; and bind to ACE2 with K D (4.08 ± 0.61)e−7 M, (2.95 ± 0.78)e−7 M, and (7.32 ± 0.42)e−7 M, respectively. As a result, SAA, SAB, and SAC were determined to inhibit the entry of 2019‐nCoV Spike pseudovirus with an EC50 of 11.31, 6.22, and 10.14 μM on ACE2h cells, respectively. In conclusion, our study revealed that three Salvianolic acids can inhibit the entry of 2019‐nCoV spike pseudovirus into ACE2h cells by binding to the RBD of the 2019‐nCoV spike protein and ACE2 protein.

Three salvianolic acids inhibit 2019‐nCoV spike pseudovirus viropexis by binding to both its RBD and receptor ACE2
https://pmc.ncbi.nlm.nih.gov/articles/PMC8013543/

For those who have become infected with COVID or have been exposed to the Spike Protein, Danshen may be a strong ally in protecting the endothelium (and the mitochondria), potentially helping protect against the endothelial dysfunction that I have described as SPED (Spike Protein Endothelial Disease).

Through this review, we found that SM has antioxidative, anti-inflammatory, and antithrombotic effects. SM can decrease ROS formation in the mitochondria, preventing endothelial cell dysfunction. Endothelial dysfunction may be related to many cardiovascular and cerebrovascular diseases, such as stroke, acute myocardial infarction, peripheral vascular disease, and Alzheimer’s disease. Both lipophilic and hydrophilic components of SM can protect the endothelium against mitochondrial oxidative stress. More research is needed to discover the mechanism of SM in preventing oxidative stress in the endothelium.

Salvia miltiorrhiza Protects Endothelial Dysfunction against Mitochondrial Oxidative Stress
https://pmc.ncbi.nlm.nih.gov/articles/PMC7179142/

As the Spike Protein is known to activate both NLRP3 and NF- κB inflammatory pathways, Danshen may be useful here too. Danshen has been shown experimentally to suppress activation of both the NF-κB pathway and the NLRP3 inflammasome and ameliorates early atherosclerosis.

Compared with the model group, the SAA (Salvianolic acid A (SAA), an important bioactive polyphenolic acid found in Salvia miltiorrhiza) high dosage (1 mg/kg) group exhibited decreased hemoglobin A1C levels but unchanged blood glucose levels. The disrupted lipid profiles were ameliorated by SAA, with significantly decreased levels of blood cholesterol, LDL-C and triglyceride. The protective effects of SAA against early AS were further confirmed by histopathological examination of aortic tissues. In addition, we observed that SAA decreased serum hs-CRP levels and suppressed the activation of NLRP3 inflammasome and NF-κB signaling in aortic tissues of ZDF rats. Collectively, our results demonstrate the potential of SAA to alleviate AS and T2DM in ZDF rats as a result of its anti-inflammatory effects.

Salvianolic Acid A Ameliorates Early-Stage Atherosclerosis Development by Inhibiting NLRP3 Inflammasome Activation in Zucker Diabetic Fatty Rats
https://pmc.ncbi.nlm.nih.gov/articles/PMC7179142/

One other therapeutic aspect worth mentioning is that a preparation containing both Astragalus membranaceus and Salvia miltiorrhiza significantly improved fatigue and brain fog scores in an observational study of patients with Long COVID. While the contribution of each herb remains uncertain, the results are encouraging and deserve further study.

Results

A total of 50 participants (18 males, 32 females) were enrolled; 49 were included in the intention-to-treat analysis with scores of 66.9 ± 11.7 on mKCFQ11 and 6.3 ± 1.5 on the brain fog VAS. After 4 weeks of MYP (myelophil, a 30% ethanol extract of Astragalus membranaceus and Salvia miltiorrhiza) administration, there were statistically significant improvements in fatigue levels: mKCFQ11 was measured at 34.8 ± 17.1 and brain fog VAS at 3.0 ± 1.9. Additionally, MFI-20 decreased from 64.8 ± 9.8 to 49.3 ± 10.8, fatigue VAS dropped from 7.4 ± 1.0 to 3.4 ± 1.7, SF-12 scores rose from 53.3 ± 14.9 to 78.6 ± 14.3, and plasma cortisol levels also elevated from 138.8 ± 50.1 to 176.9 ± 62.0 /mL. No safety concerns emerged during the trial.

Conclusion

Current findings underline MYP’s potential in managing Long COVID-induced fatigue. However, comprehensive studies remain imperative.

Evaluating myelophil, a 30% ethanol extract of Astragalus membranaceus and Salvia miltiorrhiza, for alleviating fatigue in long COVID: a real-world observational study
https://pmc.ncbi.nlm.nih.gov/articles/PMC11222562/

We have discussed yet another functional nutraceutical which I hope will be investigated further in the context of Long COVID/Spike Protein disease/injury. You keep me going. I appreciate all of your support and am grateful for everyone in our community. Please have a blessed weekend.

One-Time Donation
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

Temporal discounting.

It’s obvious that as a species we are really good at responding to immediate danger; A charging bear. A house fire. A heart attack. These command our full attention since they are immediate threats.

Yet our psychology is generally less responsive to hazards that accumulate gradually over months or years. A danger that unfolds one small step at a time often fails to trigger the same instinctive alarm—even when its cumulative impact may ultimately be substantial.

This phenomenon is well described in psychology and behavioral economics and is known as temporal discounting.

Two experiments were conducted to investigate the effects of a strategic issue’s temporal proximity on the identification of the issue as threatening or opportunity like. In Experiment 1, university students (N = 86) reacted to hypothetical threats or opportunities that differed in the degree to which they were immediate or delayed. Evidence was found for the asymmetrical discounting of strategic issues such that students discounted distant threats more than distant opportunities. In addition, it was found that, although immediate threats were viewed just as likely to occur as immediate opportunities, distant threats were seen as less likely to occur than distant opportunities.

Temporal discounting of strategic issues: Bold forecasts for opportunities and threats
https://pure.psu.edu/en/publications/temporal-discounting-of-strategic-issues-bold-forecasts-for-oppor/

Unsurprisingly, it is why it is so damn difficult for us to change our habits with an eye towards future health.

Normative discounted utility theory specifies that the values of all future outcomes (for example, those related to health and money) should be discounted at a constant rate. Two experiments demonstrated that, contrary to this prescription, decision makers use different discount rates for health-related decisions and money-related decisions. Temporal discount ings for health and money were similar in that both demonstrated two biases previously found in monetary decisions: discount rates were inversely related to magnitude of outcome and length of delay. The relatively large discount rates used by the subjects suggest why it is often difficult to implement preventive health measures that improve future health.

Valuing the Future: Temporal Discounting of Health and Money
https://journals.sagepub.com/doi/abs/10.1177/0272989X9501500408

This may explain why discussions surrounding persistent Spike Protein and Long COVID remain in a state where many – if not most – regard them as nothingburgers.

The MSM has focused solely on acute COVID-19: hospitalization, respiratory failure and immediate mortality. Vaccines were likewise touted primarily for their “ability” to reduce IMMEDIATE severe disease during the acute phase of infection. Sadly. very little has ever been said of COVID sequelae in the MSM. Other than that some people have Long COVID.

No MSM attention has been devoted to an entirely different question:

What if the principal burden of COVID is not an immediate one, but a cumulative biological one?

Many chronic diseases do not emerge overnight.

• Atherosclerosis develops over decades.

• Fibrosis progresses slowly.

• Microvascular dysfunction often begins years before symptoms become obvious.

• Neurodegenerative diseases may silently evolve for decades before diagnosis.

If persistent Spike Protein contributes—even modestly (and you know I believe it to contribute far more so)—to endothelial dysfunction, chronic inflammation, mitochondrial impairment or immune dysregulation, then the resulting disease burden may not appear until years later. Individual effects could be subtle yet repeated over time through multiple infections and Spike Protein exposures; they may gradually accumulate.

Many of the mechanisms we discuss here involved in Long COVID/Spike Protein disease/injury—including endothelial dysfunction, persistent inflammation, oxidative stress, immune dysregulation and mitochondrial impairment—are processes that unfold gradually in chronic diseases rather than catastrophically. Their consequences may only become apparent after years of cumulative injury.

I am certainly not suggesting that persistent Spike Protein is responsible for every chronic illness being investigated today. Much remains uncertain, and careful scientific inquiry is essential.

However, what I am suggesting is that our greatest blind spot may not be biological at all.

It may be psychological.

History repeatedly shows that humanity responds far more readily to crises that explode than to those that slowly unfold. The latter are easier to dismiss because each day’s change appears insignificant—even when the cumulative effect is substantial.

If persistent viral proteins contribute to chronic disease, the challenge before us is not simply one of molecular biology. It is learning to recognize that some of the most consequential threats to human health do not arrive with a bang. They arrive one deleted capillary, one dysfunctional mitochondrion and one inflammatory signal at a time.

You keep me going. I appreciate all of your support and am thankful to everyone in our community. Please have a blessed week.

One-Time Donation
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

Among nutraceuticals currently under investigation for antiviral, endothelial, mitochondrial and anti-inflammatory effects, cordycepin—the principal bioactive compound of Cordyceps—stands out because many of its reported biological activities overlap with pathways implicated in SARS-CoV-2 and Spike Protein pathology.

Cordyceps is a rare naturally occurring entomopathogenic fungus usually found at high altitudes on the Himalayan plateau and a well-known medicinal mushroom in traditional Chinese medicine. Cordyceps contains various bioactive components, out of which, cordycepin is considered most vital, due to its utmost therapeutic as well as nutraceutical potential. Moreover, the structure similarity of cordycepin with adenosine makes it an important bioactive component, with difference of only hydroxyl group, lacking in the 3′ position of its ribose moiety. Cordycepin is known for various nutraceutical and therapeutic potential, such as anti-diabetic, anti-hyperlipidemia, anti-fungal, anti-inflammatory, immunomodulatory, antioxidant, anti-aging, anticancer, antiviral, hepato-protective, hypo-sexuality, cardiovascular diseases, antimalarial, anti-osteoporotic, anti-arthritic, cosmeceutical etc. which makes it a most valuable medicinal mushroom for helping in maintaining good health.

Cordycepin for Health and Wellbeing: A Potent Bioactive Metabolite of an Entomopathogenic Medicinal Fungus Cordyceps with Its Nutraceutical and Therapeutic Potential
https://pmc.ncbi.nlm.nih.gov/articles/PMC7356751/

Of the SARS-CoV-2/Spike specific benefits of CD, the first I would like to discuss is how CD protects the endothelium. This is particularly relevant because Spike Protein has been shown to suppress SIRT3 expression, while cordycepin has independently been shown to restore SIRT3 signaling and improve endothelial mitochondrial function in experimental models.

The reduction of mitochondrial protein sirtuin protein 3 (SIRT3) has been reported to contribute to the development of T2DM by impacting mitochondrial respiration. Cordycepin is an adenosine derivative and is isolated from the culture filtrate of Cordyceps militaris. This study explored the protective effect of cordycepin on vascular impairment induced by T2DM and its properties and protective mechanism. In this study, a T2DM rat model was established. The endothelium-dependent relaxation of the thoracic aorta ring decreased in T2DM rats could be reversed by cordycepin. Next, mitochondrial impairment in human umbilical vein endothelial cells was detected by JC-1 staining. In vitro studies revealed that cordycepin plays a beneficial role in advanced glycation end product-induced endothelial mitochondrial impairment. Moreover, according to the cordycepin molecular docking analysis, cordycepin can bind to SIRT3. Cordycepin increased the expression and activation of SIRT3 in a dose-dependent manner. SIRT3 interruption blocked the protective effect of cordycepin on mitochondria in human umbilical vein endothelial cells. Cordycepin can conclusively protect vascular function impaired by T2DM, and the mechanism may potentially be involved in SIRT3 signaling pathways.

Protective Effect of Cordycepin on Impairment of Endothelial Function in Type 2 Diabetes Mellitus
https://pubmed.ncbi.nlm.nih.gov/35467807/

We found that spike protein interaction with the epithelium was sufficient to instigate these epithelial responses using a SCV2 spike pseudovirus. Specifically, we found downregulation of the mitochondrial markers SIRT3 and TOMM22. Moreover, SCV2 spike infection increased extracellular acidification and decreased oxygen consumption rate in the epithelium.

SARS-CoV-2 infection alters mitochondrial and cytoskeletal function in human respiratory epithelial cells mediated by expression of spike protein
https://pmc.ncbi.nlm.nih.gov/articles/PMC10470579/

NRP1 is a host receptor utilized by the SARS-CoV-2 Spike Protein and is also instrumental in cancer and syncytial formation in SARS-CoV-2 infection/Spike presence. CD downregulates this, which may be very helpful in fighting cancer, COVID and Spike Protein disease/injury.

As a result, we revealed that CD inhibits NRP1 expressed in cancer cells and prevents viral syncytial formation in 293T-hACE2 cells, implying the therapeutic potential for both anti-cancer and anti-viruses, including anti-SARS-CoV-2. We further found significant associations between NRP1 expressions and the tumor–immune response in immune lymphocytes, chemokines, receptors, immunostimulators, immune inhibitors, and major histocompatibility complexes in most cancer types, implying NRP1’s roles in both anti-cancer and anti-SARS-CoV-2 entry likely via immunotherapy. Importantly, CD also downregulated the expression of NRP1 from lymphocytes in mice and downregulated the expression of A2AR from the lung cancer cell line H1975 when treated with CD, implying the NRP1 mechanism probably through immuno-response pathways. Thus, CD may be a therapeutic component for anti-cancer and anti-viral diseases, including COVID-19, by targeting NRP1 at least.

Natural Product Cordycepin (CD) Inhibition for NRP1/CD304 Expression and Possibly SARS-CoV-2 Susceptibility Prevention on Cancers
https://pmc.ncbi.nlm.nih.gov/articles/PMC10745444/

Because NRP1 has been proposed as a contributor to persistent neurovascular dysfunction in Long COVID, it would be worthwhile to investigate whether cordycepin could serve as an adjunctive therapy in carefully designed clinical trials. At present, this remains a hypothesis requiring clinical validation.

Long coronavirus disease-19 (COVID-19) is a newly discovered syndrome characterized by multiple organ manifestations that persist for weeks to months, following the recovery from acute disease. Occasionally, neurological and cardiovascular side effects mimicking long COVID-19 have been reported in recipients of COVID-19 vaccines. Hypothetically, the clinical similarity could be due to a shared pathogenic role of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein produced by the virus or used for immunization. The S protein can bind to neuropilin (NRP)-1, which normally functions as a coreceptor for the vascular endothelial growth factor (VEGF)-A. By antagonizing the docking of VEGF-A to NRP-1, the S protein could disrupt physiological pathways involved in angiogenesis and nociception. One consequence could be the increase in unbound forms of VEGF-A that could bind to other receptors. SARS-CoV-2-infected individuals may exhibit increased plasma levels of VEGF-A during both acute illness and convalescence, which could be responsible for diffuse microvascular and neurological damage.

Impaired VEGF-A-Mediated Neurovascular Crosstalk Induced by SARS-CoV-2 Spike Protein: A Potential Hypothesis Explaining Long COVID-19 Symptoms and COVID-19 Vaccine Side Effects?
https://pmc.ncbi.nlm.nih.gov/articles/PMC9784975/

Downregulation of NRP1 represents one plausible mechanism by which cordycepin could exert beneficial effects, although multiple pathways—including mitochondrial protection, anti-inflammatory signaling and endothelial support—are also likely to contribute.

Taken together, the evidence suggests cordycepin acts on several biological systems that repeatedly emerge in SARS-CoV-2 research: endothelial dysfunction, mitochondrial impairment, chronic inflammation and NRP1 signaling. While none of these studies demonstrates efficacy in Long COVID patients directly, the convergence of these mechanisms makes cordycepin an intriguing candidate for further translational and clinical investigation.

As always, please remember this is a work of medical research and not medical advice. Make certain to talk with your primary care provider before using any medication or supplement.

You keep me going. I appreciate all of your support and am thankful to everyone in our community. Please have a blessed weekend.

One-Time Donation (Donor Decides Amount)
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

A Oxidative phosphorylation (OXPHOS) capacity was significantly lower in patients with long COVID (n = 25) compared to healthy controls (n = 21), and remained lower one day after induction of post-exertional malaise (PEM) in patients (Group: p = 0.003, Time: p < 0.001). B Succinate dehydrogenase (SDH) activity, a marker for mitochondrial density, was not different between groups (p = 0.06) and only reduced (p = 0.0083) after induction of post-exertional malaise in long COVID patients (n = 25) compared to healthy controls (n = 21). A typical example of the SDH activity is shown in panel C. Skeletal muscle (D) and venous (E) metabolome pathways indicate slightly higher levels of metabolites related to glycolysis, and a lower abundance of metabolites related to purine synthesis and the tricarboxylic acid (TCA) cycle, indicative of a lower reliance on oxidative metabolism in patients with long COVID (n = 25, both timepoints) as compared to healthy (n = 19, both timepoints). Faded names were not measured and shown for clarity. A higher effect size in long COVID is shown in red, lower effect size in blue. Continuous parametric longitudinal data (panels A, B, D, E) were analyzed with a generalized linear mixed model with a two-sided ANOVA. Post-hoc tests comparing each group were performed when the interaction term was significant and was performed using emmeans with BH adjustment (panels A and B). Effect sizes (D and E) were calculated with Hedges‘ g *p < 0.05; **p < 0.001; †p < 0.05 indicates a significant interaction effect. Bar: 50 μm. PEM post-exertional malaise. Box plots show the median (centerline), the first and third quartiles (the lower and upper bound of the box), and the whiskers show the 1.5× interquartile range.

Last week we discussed evidence supporting the hypothesis that the presence of the Spike Protein causes persistent microvascular destruction. This week I would like to discuss how that same persistence may be responsible for the debilitating fatigue experienced by those with Long COVID.

Fatigue is almost certainly the most common persistent symptom of Long COVID.

Fatigue was reported as one of the most common persistent symptoms in individuals infected with SARS-CoV-2 before. Persistent fatigue lasting at least 6 months is termed chronic fatigue syndrome (33). This may be observed after several viral and bacterial infections (48). In the included studies of the present systematic review, fatigue was a symptom that either occurred already in the acute phase or developed after recovery from the acute phase of infection. The included studies recruited patients for a maximum of 9 months, with fatigue as persistent symptom. This should be followed up for a longer period to see how long fatigue could persist after the acute infection of COVID-19.

Post-COVID-19 fatigue: A systematic review
https://pmc.ncbi.nlm.nih.gov/articles/PMC9403611/

Mitochondrial dysfunction is the primary driver of Chronic Fatigue Syndrome symptoms.

Our observations strongly implicate mitochondrial dysfunction as the immediate cause of CFS symptoms. However, we cannot tell whether the damage to mitochondrial function is a primary effect, or a secondary effect to one or more of a number of primary conditions, for example cellular hypoxia [30], or oxidative stress including excessive peroxynitrite [54-58]. Mitochondrial dysfunction is also associated with several other diseases and this is not surprising in view of the important role of mitochondria in almost every cell of the body, but this fact appears to have been recognised only in recent years [34, 38, 59, 60].

Chronic fatigue syndrome and mitochondrial dysfunction
https://pmc.ncbi.nlm.nih.gov/articles/PMC2680051/

As with many other viral diseases, SARS-CoV-2 causes viral mitochondriopathy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), disrupts cellular mitochondria, leading to widespread chronic inflammation and multi-organ dysfunction. Viral proteins cause mitochondrial bioenergetic collapse, disrupt mitochondrial dynamics, and impair ionic homeostasis, while avoiding antiviral defenses, including mitochondrial antiviral signaling. These changes drive both acute COVID-19 and its longer-term effects, known as “long COVID”.

Viral mitochondriopathy in COVID-19
https://www.sciencedirect.com/science/article/pii/S2213231725002794

However, in the case of Long COVID/Spike Protein disease/injury, the Spike Protein itself may be the primary driving cause of the debilitating mitochondrial-based fatigue – along with perhaps a vast majority of the symptoms.

The 24 h S1 treatment increased ATP production and mitochondrial respiration by increasing the expression of fatty-acid-transporting regulators and inducing more negative mitochondrial membrane potential (Δψm). The 72 h S1 treatment decreased mitochondrial respiration rates and Δψm, but increased levels of reactive oxygen species (ROS), mCa2+, and intracellular Ca2+. Electron microscopy revealed increased mitochondrial fragmentation/fission in AC16 cells treated for 72 h. The effects of S1 on ATP production were completely blocked by neutralizing ACE2 but not CD147 antibodies, and were partly attenuated by Mitotempo (1 µM). Conclusion: S1 might impair mitochondrial function in human cardiomyocytes by altering Δψm, mCa2+ overload, ROS accumulation, and mitochondrial dynamics via ACE2.

Spike Protein Impairs Mitochondrial Function in Human Cardiomyocytes: Mechanisms Underlying Cardiac Injury in COVID-19
https://pmc.ncbi.nlm.nih.gov/articles/PMC10046940/

As we have discussed several times before, Spike Protein is circulating freely in those with Long COVID.

Compared to people who didn’t report long COVID symptoms, those who reported persisting symptoms affecting many organ systems were approximately twice as likely to have SARS-CoV-2 proteins circulating in their blood. The research team was able to detect the spike protein and other components of the SARS-CoV-2 virus using Simoa, an ultrasensitive test for detecting single molecules. Commonly reported long COVID symptoms included fatigue, brain fog, muscle pain, joint pain, back pain, headache, sleep disturbance, loss of smell or taste, and gastrointestinal symptoms.

Study Finds Persistent Infection Could Explain Long COVID in Some People
https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/study-finds-persistent-infection-could-explain-long-covid-in-some-people

To conclude, I will present evidence that bridges last week’s post and this week’s. Muscle biopsies found that in those with Long COVID BOTH microvascular destruction and mitochondrial dysfunction were occurring simultaneously.

Succinate dehydrogenase (SDH) activity (a marker for mitochondrial content) correlated with V̇O2max in healthy controls, but not in patients (Fig. 2F). While patients had a significantly lower oxidative phosphorylation capacity (Fig. 3A, ED 5A–H), no differences were observed in SDH activity (Fig. 3B, C; Supplemental Fig. 5I, J), suggestive of qualitatively lower mitochondrial respiration rather than a lower mitochondrial enzyme activity. Collectively, our data indicate that the lower exercise capacity in long COVID patients is associated with a greater proportion of high-fatigable glycolytic fibers and lower mitochondrial function, with a possible additional limitation of a lower capillarization and the ventilatory system.

Muscle abnormalities worsen after post-exertional malaise in long COVID
https://www.nature.com/articles/s41467-023-44432-3

If persistent Spike Protein contributes both to progressive microvascular injury and impaired mitochondrial respiration, it could create a particularly damaging combination: reduced oxygen delivery together with reduced cellular ability to utilize oxygen efficiently. That combination could help explain why fatigue in Long COVID can be so profound.

I will continue to research these mechanisms while striving to discover how the Spike’s inflammatory perspective fits into all of this. Great thanks for the gnenerous donation received since Friday. You keep me going. I appreciate it and am thankful to everyone in our community. Please have a blessed week.

One-Time Donation (Donor Decides Amount)
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

• PQQ is a potent antioxidant that supports redox balance and mitochondrial function, vital for energy and health.

• PQQ contributes to lipid metabolism regulation, indicating potential benefits for energy management.

• PQQ supplementation is linked to weight control, improved insulin sensitivity, and may help prevent metabolic disorders.

• PQQ may attenuate inflammation, bolster cognitive and cardiovascular health, and potentially assist in cancer therapies.

• Future research should investigate PQQ dosages, long-term outcomes, and its potential for metabolic and cognitive health.

Given the evidence I have been discovering supporting the hypothesis that Long COVID may involve a combination of microvascular obliteration and mitochondrial dysfunction, I have sought to find natural therapeutics which may be applicable to either or both of these conditions. I have found one that offers great mitochondrial support, among many other benefits – and may be very useful in treating Spike-induced heart inflammation.

Meet PQQ: Pyrroloquinoline Quinone.

PQQ is an aromatic tricyclic o-quinone that was originally discovered as a cofactor for bacterial dehydrogenases [24]. Its chemical structure comprises 4,5-dihydro-4,5-dioxo-1H-pyrrolo [2,3-f] quinoline-2,7,9-tricarboxylic acid, existing in a redox-active o-quinone form, which can be reversibly reduced to pyrroloquinoline quinol through a semiquinone intermediate [25]. In nature, PQQ can be found in a variety of dietary sources, such as fermented soybeans, tea, fruits, vegetables, and human milk, with concentrations ranging from 3.7 to 50 ng/g [26]. The highest PQQ content has been found in fermented soybeans, at 61 ng/g. In the human diet, the daily intake of PQQ and its derivatives has been estimated to range between 0.1 and 2 mg [27,28].

Following ingestion, PQQ is rapidly absorbed in the intestine, with peak blood levels occurring within 2–3 h [29]. Smidt et al. found that in mice, at least 62% (range 19–89%) of the consumed amount is absorbed within 24 h, after which it decreases to low levels [29]. Indeed, roughly 80% of the amount absorbed is excreted in the urine after 24 h, while around 20% is retained within the tissues, mostly in the skin and kidney [28,30]. In healthy subjects, the concentrations of PQQ in plasma and urine were found to be 1.7 ± 0.6 ng/mL and 0.8 ± 0.2 ng/mL, respectively [31]. In the same study, the analysis of human tissues obtained from cadavers revealed trace amounts of PQQ in several organs, including the liver, intestine, kidney, lung, and pancreas. The highest level of PQQ was observed in the spleen (5.9 ± 3.4 ng/g wet tissue) [31].

Due to its structure, PQQ plays a pivotal role in many cellular processes, functioning as an antioxidant, a cofactor, and a regulator of numerous cellular pathways.

Metabolic and Biochemical Effects of Pyrroloquinoline Quinone (PQQ) on Inflammation and Mitochondrial Dysfunction: Potential Health Benefits in Obesity and Future Perspectives
https://pmc.ncbi.nlm.nih.gov/articles/PMC11429417/

I would like to look at two different aspects of PQQ as it pertains to dealing with the Spike Protein. First, it may help with the mitochondrial dysfunction induced by the Spike Protein.

Early in this century, PQQ was discovered as redox cofactor from human milk (He et al., 2003). Both in vitro and in vivo studies involving various animal models for human ailments revealed that PQQ is a strong antioxidant regulating mitochondrial physiology and biogenesis, and being an essential cofactor in various biological processes (Fig. 2). PQQ exhibits potent antioxidant properties by protecting the mitochondria against oxidative stress mediated lipid peroxidation (LPO), protein carbonyl formation, and avoid damages incurred to the respiratory chain (He et al., 2003; Gao et al., 2022).

Pyrroloquinoline Quinone (PQQ): Its impact on human health and potential benefits
https://pmc.ncbi.nlm.nih.gov/articles/PMC11541945/

Indeed, PQQ has already been proposed as a potential therapeutic for treating mitochondrial dysfunction in Long COVID (PCC – Post COVID Condition).

The accumulation of ROS remains a significant challenge in PCC, prompting the use of antioxidants such as NAC and vitamins C and E, which neutralize free radicals and promote glutathione regeneration, a key antioxidant in cellular defense (46, 47). Other promising compounds for restoring mitochondrial function in PCC patients include PQQ and omega-3 fatty acids. PQQ serves as a cofactor that enhances mitochondrial biogenesis through the PGC-1α pathway and possesses antioxidant properties (48). Likewise, omega-3 fatty acids have shown potential to activate PGC-1α, thereby enhancing mitochondrial resilience and adaptability (49).

Mitochondrial metabolic rescue in post-COVID-19 syndrome: MR spectroscopy insights and precision nutritional therapeutics
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1597370/full

The other Spike-related aspect of PQQ I’d like to examine is its potential to treat Spike-induced heart inflammation. This type of inflammation, of course, has caused significant morbidity and mortality and may result from any exposure to the Spike Protein.

It has been recently discovered that PQQ can prevent chronic heart failure by regulating mitochondrial function.37 As COVID-19 infection (and to some extent vaccination against COVID-19) has associated cardiovascular complications such as arrhythmias, thrombosis, heart failure, cardiomyopathy, myocardial damage, and acute coronary syndromes,38,39 through inflammatory processes linked to the SARS-CoV-2 spike protein, PQQ could likely help against these specific complications of COVID-19 infection, as well as against the side effects of COVID-19 vaccinations.

PQQ Supplementation and SARS-CoV-2 Spike Protein-Induced Heart Inflammation
https://pmc.ncbi.nlm.nih.gov/articles/PMC8905048/

I hope clinicians reading this will consider PQQ as an adjunct therapy for their Long COVID/Spike Protein injured patients. I also hope researchers with access to labs will embark on clinical trials using PQQ as a COVID/Spike Protein therapeutic. Please bear in mind, this is a work of medical research and not medical advice. Always consult your primary care provider before using any medication or supplement.

Thank you for your enthusiastic support of Monday’s post. I will continue to research and report back to you. Great thanks also to the new Paid Subscriber and several generous donors since Monday. You keep me going. And I appreciate and am thankful for everyone in our community. Please have a blessed weekend.

One-Time Donation (Donor Decides Amount)
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

Microvascular phenotyping by quantitative sublingual video microscopy. A Median and IQR values of vascular density of healthy controls (green), and long-haul COVID-19 (orange) patients based on the diameter class from 4 to 25 µm. A historical cohort of hospitalized COVID-19 patients (pink) is shown for reference. *q < 0.05, **q < 0.01, ***q < 0.001. B–D Boxplots of B capillary density (D4–6 µm) and C PBR4–25 µm and D MVHS™ of healthy controls (green), long-haul COVID individuals (orange), COVID-19 patients (pink). COVID-19 Coronavirus disease 2019, CR capillary recruitment, D diameter, PBR perfused boundary region, RBC red blood cell, VRBC red blood cell velocity, MVHS™ microvascular health score

As readers of this Substack know, my focus from the beginning has been on what I have called SPED – Spike Protein Endothelial Disease. Over the years I have continuously honed this hypothesis. In April of this year, I posited that the ultimate “goal” of the Spike Protein is to slowly erase the microvasculature – with devastating consequences. One of the most dramatic being Sudden Cardiac Death. Could SPED be the initial step in a larger disease which I shall call ASSD – Acquired Systemic Sclerosis-like Disease.”

I now present evidence that this indeed is what the Spike Protein is doing to the microvasculature. A study published in 2022 definitively gave proof that Long COVID results in persistent capillary rarefication (obliteration).

Measurements and main results

Although dimensions of the glycocalyx were comparable to those of healthy controls, a µm-precise analysis showed a significant decrease of vascular density, that exclusively affected very small capillaries (D5: − 45.16%; D6: − 35.60%; D7: − 22.79%). Plotting VRBC of capillaries and feed vessels showed that the number of capillaries perfused in long COVID patients was comparable to that of critically ill COVID-19 patients and did not respond adequately to local variations of tissue metabolic demand. MVHS was markedly reduced in the long COVID cohort (healthy 3.87 vs. long COVID 2.72 points; p = 0.002).

Conclusions

Our current data strongly suggest that COVID-19 leaves a persistent capillary rarefication even 18 months after infection. Whether, to what extent, and when the observed damage might be reversible remains unclear.

Persistent capillary rarefication in long COVID syndrome https://link.springer.com/article/10.1007/s10456-022-09850-9

Remember, the Spike Protein alone damages the endothelium.

While the findings themselves aren’t entirely a surprise, the paper provides clear confirmation and a detailed explanation of the mechanism through which the protein damages vascular cells for the first time. There’s been a growing consensus that SARS-CoV-2 affects the vascular system, but exactly how it did so was not understood. Similarly, scientists studying other coronaviruses have long suspected that the spike protein contributed to damaging vascular endothelial cells, but this is the first time the process has been documented.

In the new study, the researchers created a “pseudovirus” that was surrounded by SARS-CoV-2 classic crown of spike proteins, but did not contain any actual virus. Exposure to this pseudovirus resulted in damage to the lungs and arteries of an animal model—proving that the spike protein alone was enough to cause disease. Tissue samples showed inflammation in endothelial cells lining the pulmonary artery walls.

The team then replicated this process in the lab, exposing healthy endothelial cells (which line arteries) to the spike protein. They showed that the spike protein damaged the cells by binding ACE2. This binding disrupted ACE2’s molecular signaling to mitochondria (organelles that generate energy for cells), causing the mitochondria to become damaged and fragmented.

The novel coronavirus’ spike protein plays additional key role in illness
https://www.salk.edu/news-release/the-novel-coronavirus-spike-protein-plays-additional-key-role-in-illness/

And the Spike Protein is found circulating in those with Long COVID.

Other case reports indicate that the Spike protein can be detected in the tissues of patients with LC up to a year after infection [93,97,105,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,157,158,160,161,162,163,164,165]. One study reported that the presence of recombinant Spike protein has been detected in the blood of individuals who received the mRNA Spike protein-based vaccine up to 3 months post-vaccination, regardless of antibody titer [166]. The study employed mass spectrometry analysis of biological samples to detect the presence of specific fragments of the recombinant Spike protein in subjects who received mRNA-based vaccines [166]. The minimum and maximum times at which the Spike protein was detected after vaccination were 69 and 187 days, respectively. Other studies have also reported the persistence of the Spike protein in patients with LC for 6 [166] and 15 months post-acute COVID-19 infection, with the absence of viable virus confirmed by negative PCR and RNA assays [156]. Spike protein and nucleoprotein were both detected in the colon, appendix, ileum, hemorrhoids, liver, gallbladder, and lymph nodes from five patients who recovered from COVID-19, up to 180 days after testing negative for SARS-CoV-2 using conventional immunohistochemistry [121]. However, the study was unable to detect vRNA in some patients’ tissues, possibly due to a higher mRNA degradation rate compared to protein, and the timing of detection, which occurred after recovery from acute infection [121]. Circulating Spike protein linked to extracellular vesicles with and without vRNA fragments appeared to persist in patients with LC up to one year after acute SARS-CoV-2 infection [128,155]. Finally, a study detected the Spike protein 219 days after the original positive endoscopy in the gut lining of 15 out of 132 subjects, despite the absence of replicating SARS-CoV-2 cultured from these patients’ gut tissues, which showed viral antigen persistence [107]. Residual Spike, the protein S1 subunit, was detected in patients with LC 8 and 12 months after COVID-19 resolved [128,167]. These data suggest that the circulating Spike protein and its S1 subunit may serve as a potential biomarker for persistent viral reservoirs [128,167].

Insights into Persistent SARS-CoV-2 Reservoirs in Chronic Long COVID
https://pmc.ncbi.nlm.nih.gov/articles/PMC8757925/

When we examine what happens in those who develop Systemic Sclerosis, the obliteration of the microvasculature is the PRIMARY EVENT in the pathogenesis of Systemic Sclerosis.

Systemic sclerosis (SSc, scleroderma) is a chronic, multisystem connective tissue disorder affecting the skin and various internal organs. Although the disease is characterized by a triad of widespread microangiopathy, fibrosis and autoimmunity, increasing evidence indicates that vascular damage is a primary event in the pathogenesis of SSc. The progressive vascular injury includes persistent endothelial cell activation/damage and apoptosis, intimal thickening, delamination, vessel narrowing and obliteration. These profound vascular changes lead to vascular tone dysfunction and reduced capillary blood flow, with consequent tissue ischemia and severe clinical manifestations, such as digital ulceration or amputation, pulmonary arterial hypertension and scleroderma renal crisis.

Mechanisms in the loss of capillaries in systemic sclerosis: angiogenesis versus vasculogenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC3828842/

And ultimately, it is the outcome of this damage, including Sudden Cardiac Death and damage to the heart, lungs and kidneys that gives us context. We may now look upon Long COVID as an Acquired Systemic Sclerosis-like Disease.

Findings

Fifty-nine SSc cases (64 years, 81 % female) were matched to 59 controls (62 years, 81 % female). Myocardial fibrosis was 11-times more common in SSc (95 %CI 4–29, p < 0.01), inflammation 39-times more common (95 %CI 2–672, p = 0.01) and small vessel vasculopathy 27-times more common (95 %CI 2–485, p = 0.02), despite no difference in epicardial coronary artery disease (p = 0.24). Two-thirds of SSc cases had myocardial fibrosis with no identifiable secondary cause (e.g., coronary/valvular lesions). Pulmonary fibrosis, inflammation and vasculopathy ranged from 23 to 100-times more common in SSc. Renal fibrosis/scarring, inflammation/infiltrates and vasculopathy were 3–6-times more common in SSc. Among SSc cases, combined pathologies (≥2 of fibrosis, inflammation or vasculopathy) were seen concurrently in 31 % of hearts, 41 % of lungs and 45 % of kidneys.

Interpretation

The high frequency of unexplained myocardial fibrosis in SSc provides insights into the mechanism of excess mortality and sudden cardiac death observed in SSc. This matched autopsy study demonstrates the mechanisms and complexity of organ damage in SSc, with 30–45 % of organs displaying multiple concurrent pathologies.

Pathological contributors to organ damage and mortality in systemic sclerosis: a nationwide matched case-control study
https://www.sciencedirect.com/science/article/pii/S0049017225001106

What we must determine is whether or not this is occurring to some degree after ANY exposure to the Spike Protein. We need population-wide studies of capillary density based on COVID infection, vaccination, reinfection, antibody status and circulating Spike Protein status data.

Thank you, as always, for your continued support of my work. Your readership, dialogue and financial contributions keep the engines running and keep me inspired to continually seek understanding and share that knowledge with you. Great thanks to the generous donation received since Friday. Please have a blessed week.

One-Time Donation (Donor Decides Amount)
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

Cardiac injury associated with SARS-CoV-2 and the role of epicardial adipose tissue. EAT, epicardial adipose tissue; ACE2, angiotensin-converting enzyme 2; MVD, microvascular damage; TNF, tumour necrosis factor; IL, interleukin.

Last year we discussed how Colchicine inhibits cytokine storms and microtubules in the context of COVID/Spike Protein disease/injury.

Friday Hope: Colchicine: Inhibiting Cytokine Storms, Microtubules and the Invasion of the Spike Protein
https://wmcresearch.substack.com/p/friday-hope-colchicine-inhibiting

Today I would like to discuss how Colchicine may play a greater role in treating COVID/Spike Protein disease/injury than originally thought. In particular, Colchicine may be very effective in treating the acute cardiac effects and cardiac sequelae of COVID/Spike Protein exposure. It does this, in part, by altering the inflammatory profile of epicardial adipose tissue (EAT), located between the myocardium and visceral pericardium.

First, for those who may not have read last year’s post, a brief refresher on what Colchicine is.

Colchicum autumnale, commonly known as autumn crocus and meadow saffron, is a toxic autumn-blooming flowering plant that resembles the true crocuses, but is a member of the plant family Colchicaceae, unlike the true crocuses, which belong to the family Iridaceae. Despite the vernacular name of “meadow saffron”, this plant is not the source of saffron, which is obtained from the saffron crocus, Crocus sativus – and that plant, too, is sometimes called “autumn crocus”.

The bulb-like corms of C. autumnale contain colchicine, a useful drug with a narrow therapeutic index. Colchicine is approved in many countries for the treatment of gout and familial Mediterranean fever.

Colchicum autumnale
https://en.wikipedia.org/wiki/Colchicum_autumnale

Back to EAT and the Spike Protein. We can gain further knowledge as to why the elderly and the obese are more prone to severe COVID disease/Spike Protein pathology. A factor for adverse cardiac outcomes in these populations may be related to the amount of EAT these individuals have – and that the Spike particularly likes EAT.

The SARS-CoV-2 infection is triggered by binding of the spike protein of the virus to ACE2, which is highly expressed in the heart and lungs. From a previous experiment, ACE2 and the inflammatory cytokines tumour necrosis factor- (TNF) α and interleukin-6 (IL-6) have been demonstrated to be expressed at higher levels in EAT in heart explants removed from obese patients. We may infer that EAT would act as a major contributor for the SARS-CoV-2 entry into the heart and promote an augmented inflammatory response in the myocardium and surrounding structures, causing myocardial complications such as myocarditis and cardiac dysfunction, providing an inflammatory environment by stimulation of inflammatory cells, adipokines, and cytokines.4 The cascade of inflammatory factors such as TNF-α and IL-6 has been linked to a diminished inotropic effect and decreased cardiac function, resulting in aggravation of hypoxia and a systemic myocardial inflammatory response.3 , 4

Being elderly and being obese are common contributors to EAT and there is an increased chance of SARS-CoV-2 infections in these subjects.5 The higher prevalence of cardiac injury associated with COVID-19 in these specific populations may be linked to EAT acting as a ‘fuel for cardiac inflammation’ (Figure 1, above).

Epicardial adipose tissue: fuel for COVID-19-induced cardiac injury?
https://academic.oup.com/eurheartj/article/41/24/2334/5848376

The above inferences have been supported over time.

Our COVID-19 patients had higher EAT attenuation values than controls. Among COVID-19 patients, EAT attenuation was higher in cases with a complicated clinical course: in hemodynamically unstable patients and among those requiring intensive care and mechanical ventilation. These findings are compatible with the hypothesis that EAT could act as a contributor to SARS-CoV-2 entry into the heart and promote an augmented inflammatory response causing myocardial complications, suggested by Kim et al.

Epicardial adipose tissue attenuation in admitted patients with COVID-19
https://www.revespcardiol.org/en-epicardial-adipose-tissue-attenuation-in-articulo-S188558572100222X

How may Colchicine help? By altering EAT’s inflammatory profile.

Inflammation originating within EAT has emerged as an important, potentially modifiable substrate for atrial fibrillation, another key comorbidity in HFpEF. In a prospective clinical series of 122 patients undergoing catheter ablation, low-dose colchicine (0.5 mg daily for two weeks) did not influence early (three-month) outcomes, but it nearly halved mid-term atrial fibrillation recurrence at 12 months in those with an LA EAT volume above the cohort median of 22.4 cm3 (10.5 vs. 34.2%, p = 0.06). No benefit was observed when EAT burden was smaller [119]. These findings imply that the anti-inflammatory effects of colchicine become clinically significant only when the adipose inflammatory reservoir is substantial. Experimental work supports and extends this concept. In a mouse model of postoperative atrial fibrillation caused by lipopolysaccharide-induced acute inflammation [57], EAT-derived cytokines, neutrophil and macrophage infiltration, and a higher neutrophil-to-lymphocyte ratio created a pro-arrhythmic environment. These changes were associated with QTc prolongation, Ca2+-handling abnormalities, and increased atrial fibrillation inducibility [57]. Colchicine administered once at an intermediate dose (0.10–0.40 mg kg−1; human-equivalent ≈ 0.5 mg) normalised immune cell profiles, shortened QTc, stabilised the myocardial microtubule network, and reduced arrhythmia episodes, whereas lower or higher doses were ineffective or toxic [57]. Overall, the clinical and pre-clinical data show that EAT-driven inflammation increases the risk of early atrial fibrillation recurrence and postoperative atrial fibrillation, and that colchicine can reduce this risk if EAT volume is significant and dosing is carefully adjusted.

Beyond Traditional Risk Factors: Integrating Epicardial Adipose Tissue into the Comorbidity Landscape of HFpEF
https://pmc.ncbi.nlm.nih.gov/articles/PMC12429259/

It is my hope that clinicians and researchers reading this will further trial/study the cardiac effects of Colchicine on those suffering from Long COVID/Spike Protein disease/injury. It may help keep some from developing fatal arrhythmias or progressing to HF.

Thank you, as always, for your continued support of my work. Your readership, dialogue and financial contributions keep the engines running and keep me inspired to continually seek understanding and share that knowledge with you. Great thanks to the two new Paid Subscribers since Monday. Please have a blessed week.

One-Time Donation (Donor Decides Amount)
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

Allergic sensitization to α-Gal (A) occurs after repeated tick bites. Among immunomodulatory molecules, tick saliva contains proteins glycosylated with α-Gal and most likely also α-Gal containing glycolipids. α-Gal on proteins is recognized by memory B cells expressing anti-α-Gal B cell receptors. In contrast, glycolipids might be recognized by iNKT cells, which can then produce IL-4. B cells process the glycoproteins and present the peptides to naT cells. In the IL-4 rich milieu, T cells then induce the class switch recombination of B cells leading to the production of IgE to α-Gal, which then bind to basophils and mast cells. When sensitized individuals ingest red meat containing α-Gal bound to proteins and lipids (B), these glycolipids are incorporated into lipid micelles (C). Pancreatic lipase, an enzyme active at water-lipid interfaces, hydrolyzes the triglycerides inside the micelle into free fatty acids, mono- and diglycerides, which are absorbed by enterocytes. About 4 h later, processed lipids, packed in chylomicrons and presumably coated with α-Gal molecules, are released into the lymph via the lacteal vein. When chylomicrons reach the blood stream and tissues (D), they encounter basophils and mast cells coated with IgE antibodies to α-Gal. The α-Gal moieties displayed on the surface of chylomicrons can then cause the cross-linking of IgEs and the subsequent degranulation of basophils and mast cells leading to a systemic allergic reaction.

Much has been made in the news recently about Alpha-Gal Syndrome. This is a condition that causes the body to have a severe allergic reaction to red meat. A study published by some Michigan researchers enraged the sane people of this world when they argued that bioengineering and releasing ticks that cause Alpha-Gal is MORALLY OBLIGATORY.

There is a great medical lesson to learn here, however. For, what is the mechanism that causes a tick to make one allergic to red meat? The mechanism involves REPEATED EXPOSURES. And this is where it becomes extremely relevant to the dangers of the Spike Protein – regardless, I propose, of Spike Protein source.

Alpha-gal syndrome (AGS) is an allergy characterized by hypersensitivity to mammalian meat. Patients suffering from the syndrome develop IgE antibodies against galactose-α-1,3-galactose (alpha-gal), a carbohydrate found in non-primate mammal cells [1]. The mechanism behind the development of the allergy is thought to be mediated by tick bites. In America, specifically, the lone star tick has been identified as a significant agent [2]. Sensitization is believed to involve repeated exposures that introduce alpha-gal-containing proteins and trigger IgE-mediated immune responses [3].

Alpha-Gal on the Rise: The Alarming Growth of Alpha-Gal Syndrome in High-Risk Regions
https://pmc.ncbi.nlm.nih.gov/articles/PMC12365936/

Long COVID, or PASC (Postacute Sequelae of COVID) is critical here as repeated acute COVID infections are cumulatively likely to induce PASC.

First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs’ national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR) = 2.17, 95% confidence intervals (CI) 1.93–2.45), hospitalization (HR = 3.32, 95% CI 3.13–3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections.

Acute and postacute sequelae associated with SARS-CoV-2 reinfection
https://www.nature.com/articles/s41591-022-02051-3

It is astounding to me that autoimmune disorders were NOT one of the sequalae tracked in the above study: sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders.

After all, the likelihood of autoimmunity after ONE COVID infection is well documented.

We calculated overall and infection severity-stratified incidence ratesper 1000 person-years for all autoimmune diseases. With least severe COVID-19 severity as reference, survival analyses examined incident autoimmune disease risk. The most common new-onset autoimmune diseases in all networks were thyroid disease, psoriasis/psoriatic arthritis, and inflammatory bowel disease. Among adults, inflammatory arthritis was the most common, and Sjögren’s disease also had high incidence. Incident type 1 diabetes and hematological autoimmune diseases were specifically found in children. Across networks, after adjustment, patients with highest COVID-19 severity had highest risk for new autoimmune disease vs. those with least severe disease (N3C: adjusted Hazard Ratio, (aHR) 1.47 (95%CI 1.33–1.66); PCORnet aHR 1.14 (95%CI 1.02–1.26); PEDSnet: aHR 3.14 (95%CI 2.42–4.07)]. Overall, severe acute COVID-19 was most strongly associated with autoimmune disease risk in three EHR networks.

Severity of acute SARS-CoV-2 infection and risk of new-onset autoimmune disease: A RECOVER initiative study in nationwide U.S. cohorts
https://pmc.ncbi.nlm.nih.gov/articles/PMC12136303/

Severity alone, reinfection is not considered. Nor can I find any study to date that examines reinfection as a factor in developing autoimmune disease. Clearly, we need this to be investigated. Alpha-gal demonstrates a principle of immune sensitization that may help generate hypotheses regarding repeated Spike Protein exposures and autoimmunity.

If any researchers with a lab would be interested in conducting a murine study examining if autoimmunity develops post multiple infection/mRNA Spike exposures, please contact me.

Thank you, as always, for your continued support of my work. Your readership, dialogue and financial contributions keep the engines running and keep me inspired to continually seek understanding and share that knowledge with you. Please have a blessed week.

One-Time Donation (Donor Decides Amount)
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

Diagrammatic representation of one generic cell showing how different natural molecules could inhibit multiple targets of SARS-CoV-2. Luteolin and eriodictyol would inhibit both ACE2 and TLR4, while oleuropein, hydroxytyrosol, and sulforaphane would inhibit the serine esterases and RNA polymerases, as well as the mammalian target of rapamycin (mTOR) and the inflammasome. Black arrows indicate activation, green T lines indicate inhibition, blue arrows indicate outcomes, and red arrows indicate secretion extracellularly.

Once again, we return to the Mediterranean Diet for one of its staples. Olives! Needing no introduction, Olives are one of the OGs of natural medicine. Indeed, their medicinal qualities have been known for thousands of years.

The curative powers of olive oil were already known in Ancient Egypt. The Ebers Papyrus is a medical text dating back to around 1,550 BCE. It contains recipes and remedies for various ailments, many of which involve the use of oils and ointments made from plants and other natural materials, including olive oil. There are recipes for ointments made with olive oil to treat skin conditions such as eczema and psoriasis, as well as to soothe insect bites and stings. It is also mentioned as a treatment for joint pain and eye infections. Even the Greeks believed that olive oil had medicinal properties, and it was recommended to treat skin conditions, digestive disorders and more. A mixture of olive oil combined with other oils was also used by Greek women as a form of birth control (5). Olive oil as a remedy for a number of ailments can be found in Traditional Persian Medicine (TPM). The Canon of Medicine (Al-Qanun fi al-Tibb), written by Avicenna (Ibn Sina) in the 11th century, mentions the use of olive oil for digestion, respiratory problems, skin diseases, joint pains, fevers, but also for mental health. Avicenna believed that olive oil had a calming effect on the nervous system and could be used to treat anxiety and depression. The Canon of Medicine is in many ways a synthesis of the medical knowledge of the ancient Greeks and the medical practices of the Islamic world. It drew extensively from the works of Hippocrates, Galen, and other ancient Greek physicians, as well as from the medical traditions of Persia, India, and other regions.

From antiquity to contemporary times: how olive oil by-products and waste water can contribute to health
https://pmc.ncbi.nlm.nih.gov/articles/PMC10615083/

In the context of COVID, Long COVID and Spike Protein pathology, Olives also appear to continue this long and storied history of medicinal use. Let’s break it down into the several ways Olive can help us in our fight against SARS-CoV-2 and its Spike Protein. This help comes in two forms; the fruit itself and the leaves.

First, let’s look at the fruit. A study in 2023 found remarkable benefits in a group of patients who took at least 50 milliliters of OO (Olive Oil) daily vs patients who did not.

Results: There were no age and gender differences between groups (p=0,266 and p=0.986, respectively). In addition, serum creatinine, serum glucose and lymphocyte levels were similar between groups at the first day of hospitalization (p=0,546; p=0.607 and p= 0.787; respectivelly). Compared to OO group, length of stay was longer in non-OO group [8 days (7 - 9) versus 24 days (20 - 29); p=0.001]. Furthermore, patients who taken OO have less required ICU than those did not get OO [11 (17.7% versus 26 (74.3%) p=0.001)]. While 6 (9.7%) patients were died in OO group, 14 (40.0%) patients were died among patients in non-OO group (p=0.001).

Conclusion: It can be concluded that olive oil consumption is capable to reduce mortality rates and is beneficial in cases with COVID-19 infection. This unique phenomenon may have been related to phytochemical compounds and polyphenol constituents of Turkish olive oil. Further studies are warranted.

Olive Oil Protection Against Covid-19 Infection. Aegean Miracle.
https://www.clinicalnutritionespen.com/article/S2405-4577(22)00993-7/fulltext

Now add Olive Leaf Extract (OLE) as a therapeutic. The results are also impressive. What I find particularly interesting is that OLE use resulted in a significant lowering of the heart rate during a COVID infection. This could also be relevant to those suffering from Long COVID.

Results

Of the 150 patients randomized into groups, 141 completed the follow-up and were analyzed. On the fifth day of hospitalization, body temperature (MD=0.34, P<0.001), pulse rate (MD=5.42, P=0.016), respiratory rate (MD=1.66, P=0.001), ESR (MD=13.55, P<0.001), and CRP (MD=15.68, P<0.001) of intervention A were significantly lower than the control group, while oxygen saturation (MD= -1.81, P=0.001) of intervention A was significantly higher than the control group. Furthermore, body temperature (MD=0.30, P=0.001), pulse rate (MD=5.29, P=0.022), respiratory rate (MD=1.41, P=0.006), ESR (MD=14.79, P<0.001), and CRP (MD=16.28, P<0.001) of intervention B were significantly lower than the control group, while oxygen saturation (MD= -2.38, P<0.001) of intervention B was significantly higher than the control group.

Conclusion

Olive leaf extract can improve the clinical status of the patients and decrease the length of hospitalization.

Efficacy of olive leaves extract on the outcomes of hospitalized covid-19 patients: A randomized, triple-blinded clinical trial
https://pmc.ncbi.nlm.nih.gov/articles/PMC9617633/

Compounds derived from all parts of the Olive tree have come into focus as a potential therapeutic for those suffering from Long COVID, particularly NeuroCOVID.

As presented herein, the olive tree produces key bioactive compounds with neuroprotective properties that can be proven effective in the management of conditions affected by neuroinflammation and cognitive decline. In the absence of any published benefit of repurposed drugs, investigating the use of high-quality dietary supplements for long COVID is a prudent next step, as they are safe and potentially quite effective [254,276,293,294,295].

Environmentally and economically sustainable procedures could be applied to olive oil processing on an industrial scale [296], yielding high-purity isolates [297] with neuroprotective benefits, as evident by this review and other clinical studies [13,298,299]. The use of Machine learning and NMR in the detection and quantification of phenolic compounds is also promising [170,300].

Given the findings discussed above, it appears that all complex disorders reviewed involve neurovascular inflammation that may benefit from the introduction of Olea europaea L. polyphenols.

Anti-Inflammatory and Neuroprotective Polyphenols Derived from the European Olive Tree, Olea europaea L., in Long COVID and Other Conditions Involving Cognitive Impairment
https://www.mdpi.com/1422-0067/25/20/11040

In broader terms, the inflammation associated with aging and general Spike exposure may be ameliorated by using Olive tree products. This includes, importantly, treating senescent endothelial cells.

Olive tree by-products have been deeply studied as an invaluable source of bioactive compounds. Several in vitro and in vivo studies showed that olive leaf extract (OLE) has anti-inflammatory and antioxidant properties. Here, we wanted to assess the valuable benefits of two less-studied OLE components—3,4-DHPEA-EDA (Oleacin, OC) and 3,4-DHPEA-EA (Oleuropein-Aglycone, OA)—directly purified from OLE using a cost-effective and environmentally sustainable method, in line with the principles of circular economy. OLE, OC and OA were then tested in human cellular models involved in acute and chronic inflammation and in the pathogenesis of viral infections, i.e., lipopolysaccharide (LPS)-treated monocyte/macrophages (THP-1) and endothelial cells (HUVECs), senescent HUVECs and Poly(I:C)-treated small airway epithelial cells (hSAECs). Results showed that OC and OA are efficient in ameliorating almost all of the pro-inflammatory readouts (IL-1β, TNF-α, IL-8, ICAM, VCAM) and reducing the release of IL-6 in all the cellular models. In hSAECs, they also modulate the expression of SOD2, NF-kB and also ACE2 and TMPRSS2, whose expression is required for SARS-CoV-2 virus entry. Overall, these data suggest the usefulness of OLE, OC and OA in controlling or preventing inflammatory responses, in particular those associated with viral respiratory infections and aging.

Anti-Inflammatory Effects of Olive Leaf Extract and Its Bioactive Compounds Oleacin and Oleuropein-Aglycone on Senescent Endothelial and Small Airway Epithelial Cells
https://pmc.ncbi.nlm.nih.gov/articles/PMC10451521/

I definitely have a newfound reverence for that bottle of EVOO I reach for most every time I cook. And just another example of how eating REAL FOOD may be one of the best courses of action we can take facing the Spike Protein, disease in general and ageing itself.

Thank you, as always, for your readership, dialogue and support. If you find my work thought-provoking, please consider financially supporting it as I am independent (proudly so) and not on the payroll at any institution. As I will always state with great thanks: I cannot do this without you. Please have a blessed weekend.

One-Time Donation (Donor Decides Amount)
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

Overview of adipocytes dysfunction in obesity. IR, insulin receptor; FFA, free fatty acids; TAG, triacylglycerols; ACC, acetyl-CoA carboxylase, TNF-α, tumor necrosis factor α; IL6, interleukin 6; LCACoA, long chain acyl-CoA; DAG, diacylglycerols.

There have been multiple reports of new onset diabetes after COVID and after Spike Protein mRNA.

Post-viral new-onset diabetes has been an important feature of the COVID-19 pandemic. It is not always clear if new-onset diabetes is the unmasking of a previously undiagnosed condition, the acceleration of prediabetes, or new-onset diabetes that would not have otherwise occurred. Even asymptomatic cases of COVID-19 have been associated with new-onset diabetes.

Exploring the Implications of New-Onset Diabetes in COVID-19: A Narrative Review
https://pmc.ncbi.nlm.nih.gov/articles/PMC9894635/

During the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 vaccination-induced hyperglycemia and related complications have been reported. However, there have been few reports of type 1 diabetes triggered by COVID-19 vaccines in subjects without diabetes. Here, we report the case of a 56-year-old female patient who developed hyperglycemia after the second dose of COVID-19 mRNA-based vaccination without a prior history of diabetes. She visited our hospital with uncontrolled hyperglycemia despite administration of oral hyperglycemic agents. Her initial glycated hemoglobin level was high (11.0%), and fasting serum C-peptide level was normal. The fasting serum C-peptide level decreased to 0.269 ng/mL 5 days after admission, and the anti-glutamic acid decarboxylase antibody was positive. The patient was discharged in stable condition with insulin treatment. To our knowledge, this is the first case of the development of type 1 diabetes without diabetic ketoacidosis after mRNA-based COVID-19 vaccination, and is the oldest case of type 1 diabetes development under such circumstances.

Adult-Onset Type 1 Diabetes Development Following COVID-19 mRNA Vaccination
https://pmc.ncbi.nlm.nih.gov/articles/PMC9829515/

Clearly, the incidence of Diabetes in an individual is due to multiple factors. However, let’s look at a mechanism of the Spike Protein that may give us some insight as to why some are developing new onset Diabetes after COVID or after receiving Spike Protein mRNA.

The mechanism we will examine is the Spike Protein’s ability to greatly increase the expression of (among many other proteins) IL-6 and TNF-α. This may serve as an explanation for the observed cases of new onset Diabetes. We will also examine how this is potentially directly tied to adipose tissue, which is, of course, excessive in the Obese.

First, the evidence that IL-6 and TNF-α expression are involved in the development of Diabetes.

Results: The expressions of candidate cytokines (TNF-α, IL-6, CRP, and WBC) were highly significant (p<0.001) in T2DM. Among inflammatory mediators, TNF-α shows a positive correlation (p<0.001) with glycemic profile and insulin sensitivity in T2DM cases in comparison with healthy normal. Biochemical (fasting sugar, HbA1c, insulin resistance, lipid profile) and anthropometric (BMI) parameters were highly significant (p<0.001) in T2DM cases as compared to non-diabetic normal.

Conclusion: Low grade inflammation and up regulation of inflammatory mediators has been purported to play a significant role in pathogenesis of T2DM. Our findings confirm that positive correlation of TNF-α and IL-6 with T2DM and insulin sensitivity. These can act as early prediction biomarkers of T2DM. Further studies on wider range of pro and anti- inflammatory cytokines i.e. mediators, in association with other biochemical, immunoassay and hematological parameters are needed to help clinicians manage and treat T2DM effectively.

Role of inflammatory mediators (TNF-α, IL-6, CRP), biochemical and hematological parameters in type 2 diabetes mellitus patients of Kashmir, India
https://pmc.ncbi.nlm.nih.gov/articles/PMC7139256/

Now, let’s look at how Obesity increases the levels of IL-6 and TNF-α.

TNF-α is a proinflammatory cytokine produced by macrophages, monocytes, adipose tissue [125], and skeletal muscles [126]. Acting in an auto- or paracrine manner, it affects the regulation of carbohydrate and lipid metabolism and is involved in the induction of insulin resistance [127]. Overexpression of TNFα, occurring, e.g., as a result of an increased supply of fatty acids to the cell, was first demonstrated in adipose tissue in obese and diabetic rodents [125]. These results have been confirmed in later studies showing that increased TNF-α production in human adipocytes is positively correlated with obesity, insulin levels, and insulin resistance [128].

Interleukin 6 (IL-6) is a cytokine produced in the immune system cells. It participates in inflammation, defense mechanisms, and response to mechanical injuries [134]. Approximately one third of the circulating IL-6 comes from adipose tissue [135]; however, most IL-6 originating from fat tissue is secreted by the SVF consisting of endothelial cells, macrophages, and fibroblasts [94]. The synthesis and secretion of IL-6 in the visceral tissue is almost three times higher than in the subcutaneous tissue [136].

Obesity, Bioactive Lipids, and Adipose Tissue Inflammation in Insulin Resistance
https://www.mdpi.com/2072-6643/12/5/1305

What is really important here is that the Spike Protein increases existing adipose tissue expression of IL-6 and TNF-α. In other words, this increased expression MIMICS excess adipose tissue – it mimics Obesity. So, now we may also further understand why being Obese is a risk factor for severe COVID.

METHODS: The human adipocytes were isolated from obese donor subcutaneous adipose tissue and infected with the subunit S1 spike protein from SARS-Cov-2. The adipocytes were later treated with either hrsACE2 or losartan. The levels of ACE2 and inflammatory cytokines interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were measured using enzyme linked immunosorbent assay (ELISA). ACE2 and S1 spike protein binding assays were also performed.

RESULTS: ACE2, IL-6, and TNF-α levels were significantly increased in human adipocyte cells infected with SARS-Cov-2 but not IL-1β. There was a statistically significant positive correlation between ACE2 and IL-6 (r=0.878, p<0.001). Administration of losartan and hrsACE2 was shown to reduce ACE2 levels and its binding to the SARS-CoV-2 S1 spike protein, and IL-6 levels were statistically significant, but had no significant effect on IL-1β or TNF-α levels.

CONCLUSION: This study shows that the administration of losartan in COVID-19 may not be harmful, but instead has a protective effect similar to that of hrsACE2 in preventing a cytokine storm, especially IL-6.

Losartan Has a Comparable Effect to Human Recombinant ACE2 in Reducing Interleukin-6 (IL-6) Levels on Human Adipocytes Exposed to SARS-CoV-2 Spike Protein
https://inabj.org/index.php/ibj/article/view/2552

Ultimately, what is Obesity? A Chronic Disease. We discover example after example of the Spike Protein either inducing or accelerating chronic disease – all associated with low level, chronic inflammation.

To Ponder: Is the Spike Protein the straw that breaks the camel’s back for those with chronic conditions? Does it relentlessly push us all into a position to have our backs “broken?”

Thank you, as always, for your readership, dialogue and support. As I always maintain, I cannot do this without you. This past week I received an extremely generous donation for which I am immensely grateful. Thank you. I will continue to work and report back to you. Please have a blessed week.

One-Time Donation (Donor Decides Amount)
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

Conceptual model of the link between sleep deprivation and cardiovascular disease. Sleep deprivation leads to inflammation, oxidative stress, autonomic nervous system dysregulation, and chronobiological disruption, which impair endothelial function and may lead to accelerated vascular aging and cardiovascular disease. SNS, sympathetic nervous system; PNS, parasympathetic nervous system; CVD, cardiovascular disease.

We often discuss things we can take to help us in our battle against SARS-CoV-2 and its Spike Protein. However, equally important are things we can DO. Three years ago, we discussed how sleep was a determining factor in mitigating COVID severity.

Friday Hope: Maintaining a Healthy Sleep Schedule May Attenuate COVID-19 Severity: More Evidence for Melatonin
https://wmcresearch.substack.com/p/friday-hope-maintaining-a-healthy

Today I would like to discuss how a healthy sleep schedule is perhaps as beneficial to our endothelium and maintaining healthy cytokine levels as any supplement or dietary action we have reviewed. To start, it is important to remember that proper sleep is as essential as literally anything when it comes to preventing/treating chronic disease. Especially the diseases of aging.

Sleep deprivation is one of the top modifiable risk factors to human health. The American Heart Association and CDC advocate that adults receive at least 7 h of sleep each night to promote optimal health and reduce the risk for disease [1, 2]. In agreement with this, the National Sleep Foundation recommends that adults obtain 7–9 h of sleep per night [3], yet nearly 50% fail to meet this recommendation [4]. Sleep deprivation is also an important issue in the elderly, over half of whom report sleep complaints including a diminished ability to achieve sufficient sleep duration and quality [5], which is likely secondary to the effects of age-related chronobiological disruption [6–8]. The consequences of insufficient sleep are far from benign. Indeed, there is compelling evidence that reduced sleep duration and poor sleep quality both dramatically increase the morbidity and mortality associated with cardiovascular disease (CVD) [2, 9–12], the leading cause of death in the USA [13]. Importantly, aging, a recognized CVD risk factor [14], may act in concert with insufficient sleep to accelerate cardiovascular aging and increase CVD risk. Promoting successful cardiovascular aging may start with extending the same consideration to sleep as has been given to other traditional CVD risk factors (e.g., hypertension, dyslipidemia, obesity, and physical inactivity) [15].

Effects of sleep deprivation on endothelial function in adult humans: a systematic review
https://pmc.ncbi.nlm.nih.gov/articles/PMC8050211/

Sleep deprivation causes many of the same inflammatory effects as the Spike Protein. We observe vascular inflammation, ROS production, and chronic low-grade inflammation.

Sleep is an important modulator of the immune system and thus, sleep deprivation may cause endothelial dysfunction in part by increasing vascular inflammation and reactive oxygen species (ROS) production [92]. Inflammation due to acute or chronic sleep deprivation could be the result of a chronically elevated sympathetic stress response and increased blood pressure. While blood pressure normally dips 10–20% during nighttime sleep, absence of dipping or elevations in blood pressure during sleep deprivation activate the endothelium, causing the release of inflammatory mediators, vascular adhesion molecules, and factors promoting coagulation that contribute to endothelial dysfunction [93]. This would also explain why chronic sleep deprivation, by preventing resolution of this inflammatory response, is associated with chronic low-grade inflammation and inflammatory diseases [93, 94].

Effects of sleep deprivation on endothelial function in adult humans: a systematic review
https://pmc.ncbi.nlm.nih.gov/articles/PMC8050211/

This is important. Why? Because it supports a hypothesis that exposure to the Spike Protein may induce a low-grade, barely perceptible level of chronic inflammation which may be sub-clinical – initially. When coupled with other factors, such as chronic sleep deprivation, this low level of added inflammatory stress over time then becomes clinical. This is why we need population wide studies of inflammatory biomarkers by vaccination status, SARS-CoV-2 infection history and presence or absence of circulating Spike Protein.

It is also important to note that too much sleep is also a cause of excess inflammation – particularly of cytokines which the Spike Protein is adept at influencing. For every hour of sleep over nine hours, there is a noted steady increase in IL-6 and CRP.

Results:

In this cohort, mean (SD) habitual sleep duration based on self-report was 7.6 (1.6) h and mean sleep duration by polysomnography (PSG) on the night prior to blood sampling was 6.2 (1.3) h. After adjusting for obesity and apnea severity, each additional hour of habitual sleep duration was associated with an 8% increase in C-reactive protein (CRP) levels (P = 0.004) and 7% increase in interleukin-6 (IL-6) levels (P = 0.0003). These associations were independent of self-reported sleepiness. In contrast, PSG sleep duration was inversely associated with tumor necrosis factor alpha (TNFα) levels. For each hour reduction in sleep, TNFα levels increased by 8% on average (P = 0.02). Sleep duration was not associated with IL-1 or IL-10.

Conclusions:

Increases in habitual sleep durations are associated with elevations in CRP and IL-6 while reduced PSG sleep duration is associated with elevated TNFα levels. Activation of pro-inflammatory pathways may represent a mechanism by which extreme sleep habits affect health.

Sleep Duration and Biomarkers of Inflammation
https://pmc.ncbi.nlm.nih.gov/articles/PMC2635584/

So, it is important to keep our sleep habits out of extreme ranges. Not only in the context of COVID and the Spike Protein, but for our overall health and longevity in general. Obviously, there will be days in our lives when we get too little or too much sleep. However, it is a consistent pattern of either sleep deprivation or excessive sleep that can contribute to endothelial damage and elevated cytokine levels. Much like how persistent presence of the Spike Protein can do the same.

Thank you, as always, for your readership, dialogue, and support. As I always maintain, I cannot do this without you. Please sleep well, all. And please have a blessed weekend.

One-Time Donation (Donor Decides Amount)
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

Effects of COVID-19 vaccination (VAC) on ex vivo immune readouts. (A–C) Ex vivo interleukin (IL)-6 secretion [pg/ml] from isolated PBMCs under basal conditions (A), in the presence of the T cell-specific mitogen concanavalin A (ConA; B) and in the presence of bacterial lipopolysaccharide (LPS; C). (D–F) Ex vivo IL-10 secretion [pg/ml] from isolated PBMCs under basal conditions (D), in the presence of ConA (E) and in the presence of LPS (F). Data are presented as mean + SEM including individual values. **P ≤ 0.01, ***P ≤ 0.001 versus respective participants not vaccinated against SARS-CoV-2 (noVAC).

One interesting fact about the cytokine IL-6 is that it is a biomarker for cardiovascular disease and accelerating epigenetic ageing. Let’s look at a study from 2018, which showed that IL-6 significantly increased across the entire eighth decade of life (70s) in the subjects studied. The authors viewed it as perhaps being a more reliable measure of inflammation.

As the trajectories of the inflammatory biomarkers were complex, it is difficult to determine which is most representative. IL-6, which showed a significant increase, may be a more indicative or reliable measure of inflammation, but as it was only available for two time-points we focused our analyses on CRP.

Trajectories of inflammatory biomarkers over the eighth decade and their associations with immune cell profiles and epigenetic ageing
https://link.springer.com/article/10.1186/s13148-018-0585-x

And, that inflammation is indicative of a faster running epigenetic clock.

The dynamics of the assessed inflammatory markers did not conclusively confirm an increased inflammatory state with older chronological age. We found, however, that a faster running epigenetic clock, as measured by extrinsic epigenetic age acceleration, associated with a raised inflammatory profile cross-sectionally.

Trajectories of inflammatory biomarkers over the eighth decade and their associations with immune cell profiles and epigenetic ageing
https://link.springer.com/article/10.1186/s13148-018-0585-x

Inflammation is also, of course, a pathophysiological link between cardiovascular health and ageing. In particular, proinflammatory cytokines (PICs) increase expression throughout life and correlate with poor cardiovascular outcomes. IL-6 is one of them.

We argue that increased concentrations of circulating PICs are not only markers of chronic low-grade inflammation, but they also serve as an important pathophysiological link between CV health and ageing. We discuss how PICs: 1) promote autonomic imbalance and sympathoexcitation; 2) enhance electrical instability of the myocardium, stimulate remodeling, and depress cardiac function; 3) prompt endothelial dysfunction, vasoconstriction, and progression of atherosclerosis; 4) impair renal function. All of these processes contribute to accelerated ageing of the CV system and increased susceptibility to CV morbidity and death.

Proinflammatory cytokines and ageing of the cardiovascular-renal system
https://www.sciencedirect.com/science/article/abs/pii/S0047637418300605

Why is this important in the context of COVID and Spike Protein gene therapy? Because IL-6 is ASTRONOMICALLY elevated by the Spike Protein (see opening illustration above). And it may not be a transient elevation.

Although a more detailed investigation of this phenomenon with longer time periods between vaccination and ex vivo PBMC stimulation is critically required, a lack of correlation of the time period between the 1st, 2nd and 3rd vaccination and the ex vivo IL-6 secretion from isolated PBMCs under ConA conditions (1:200 dilution of supernatants) supports the hypothesis that the here revealed vaccination effect is a non-transient one.

COVID-19 vaccination exacerbates ex vivo IL-6 release from isolated PBMCs
https://www.nature.com/articles/s41598-023-35731-2

Now, about those IL-6 levels. As we discussed earlier, those biomarker levels associated with poor CV outcomes and accelerated epigenetic clocks gradually increase in one’s seventies. Indeed, they may double from 2.x pg/ml to 4.x pg/ml.

Spaghetti plots of change in CRP and IL-6 over time. CRP: C-reactive protein; IL-6: interleukin-6; hs: high-sensitivity; ls: low-sensitivity; log(): log-transformed

Compare that to the VAC group in the initial figure above: more than 400 pg/ml of basal ex vivo IL-6 secretion. In contrast, the noVAC group exhibited minimal IL-6 secretion. While these measurements were obtained from isolated cells ex vivo rather than directly from blood plasma, they nevertheless demonstrate a markedly increased capacity for IL-6 production in immune cells obtained from vaccinated individuals.

Less striking, though still very important, a four-to-five-fold increase in IL-6 levels was also found in patients with Long COVID.

We demonstrated that increased IL-6 is associated with long COVID-19. This study suggests a mean value of IL-6 estimated at 20.92 pg/ml for long COVID-19. Collectively, findings from this study suggest high levels of this immune mediator as a basic determinant for long COVID-19, which could serve as a predictor of long COVID-19 or at least could inform on the “early stage” of long COVID-19. However, it is unclear whether comorbidities facilitate an increase in the levels of IL-6 in COVID-19 subjects. Exploratory studies need to be conducted in this regard in the future.

Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis
https://pmc.ncbi.nlm.nih.gov/articles/PMC10123579/

Clearly, this is all preliminary, and further studies are needed. General population studies of IL-6 levels over time should be a priority in this COVID/Spike Protein era. However, what we have discussed does offer a very plausible explanation for the increased CV disease being observed and the seeming accelerated ageing of many individuals.

Thank you, as always, for your dialogue, readership, and support. It is a certain fact. I cannot do this without you. And I am immensely grateful that I am able to work with your support. Please have a blessed week.

One-Time Donation (Donor Decides Amount)
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

Cumulative hazard for cardiac mortality (a, c) and sudden cardiac death (b, d): all patients (a, b) or patients with LVEF ≥ 25% (c, d) (from [40]). LVEF left ventricular ejection fraction

Given the observed actions of the Spike Protein to induce arrhythmias and heart failure, Hawthorn may prove to be a very valuable ally in preventing and treating these deleterious effects of the Spike Protein. Adding the Spike Protein’s “superb” ability to assault the Endothelium, Hawthorn presents itself very strongly as a therapeutic candidate.

In vitro experiments with human myocardial tissue demonstrated a positive inotropic effect of WS 1442 (a dry extract from hawthorn leaves with flowers) and a concentration-dependent increase of myocardial contractility accompanied by a transient rise in intracellular calcium [11, 12]. The effect is likely mediated by cyclic adenosine monophosphate (cAMP)-independent inhibition of sodium-potassium-ATPase, and is accompanied by an improved energy turnover of myocytes [12–14]. In contrast to cardiac glycosides, WS 1442 prolongs the action potential and the refractory period, and possesses pronounced anti-arrhythmic properties [15]. WS 1442 enhances the relaxant effect of the nitric oxide (NO) donor nitroprusside and increases the release of NO from the endothelium while possibly inhibiting the NO degradation due to the antioxidative properties of WS 1442 [16]. The extract causes endothelium-dependent vasorelaxation by an NO-mediated mechanism via endothelial NO synthase (eNOS)-phosphorylation at serine 1177 [17, 18]. Increased endothelial NO availability delays activation of the local angiotensin system and endothelial senescence [19]. Endothelium-derived hyperpolarizing factor contributes to the vasorelaxing activity of WS 1442, most likely due to reduced vascular oxidative stress [20]. Moreover the compound enhances microcirculation by reducing endothelial surface layer height and stiffness [21] as well as by increasing red blood cell (RBC) NO formation [22] and RBC surface negativity [23]. Chronic administration of WS 1442 leads to a dose-dependent increase in myocardial basal vessel blood flow [24] and prevents deoxycorticosterone acetate (DOCA) salt-induced hypertension and alterations of cardiac, vascular, and renal structure and function [25].

Benefit-Risk Assessment of Crataegus Extract WS 1442: An Evidence-Based Review
https://pmc.ncbi.nlm.nih.gov/articles/PMC5772138/

But, what is Hawthorn? Well, it’s been in use for literally thousands of years – and for good reason.

Crataegus sp., commonly known as hawthorn, or hawberry, is a large genus of thorny shrubs and trees belonging to the family Rosaceae, comprising approximately 280 species, native to zones with a mild climate in Europe, East Asia, and North America (Hobbs and Foster, 1994). Hawthorn has been used for centuries worldwide as both food and folk medicine. Hawthorn is one of the recognized medicinal plants in European medicine, as Dioscorides primarily described its cardiovascular actions in the first century (Petrovska, 2012). Currently, countries such as China, Germany, and France have officially recorded some species in their pharmacopeias (Chang et al., 2002).

In China, the bright red berries of hawthorn, also called Shanzha ( Figure 1 ), have been extensively used to treat various ailments given their medicinal properties. It was mentioned first for “treating dysentery” in Tang Materia Medica (Tang Ben Cao) dating back to 659 AD, the first known official pharmacopeia in the world. As described in the Compendium of Materia Medica (Bencao Gangmu), which is regarded as the most complete and comprehensive herbal monograph, the dried berry of Crataegus pinnatifida was described with healing efficacy for thoracalgia, hernia, indigestion, blood stagnation, and hematochezia (Liu et al., 2011). Currently, considerable efforts are underway to identify bioactive components from different parts of the plants and to unveil potential mechanisms of their pharmaceutical actions.

Roles and Mechanisms of Hawthorn and Its Extracts on Atherosclerosis: A Review
https://pmc.ncbi.nlm.nih.gov/articles/PMC7047282/

The anti-arrhythmic effect of Hawthorn may be particularly helpful for those suffering from Long COVID and/or recent/chronic Spike Protein exposure.

During 2 years of treatment, cumulative first cardiac event rates were lower with WS 1442 compared to placebo, albeit without reaching statistical significance (Fig. 1). Moreover, participants treated with WS 1442 were at a lower cumulative risk of cardiac mortality and sudden cardiac death (Fig. 2), notably in patients with baseline LVEF between 25 and 35% (upper limit for inclusion). In this subset, the difference with respect to placebo was descriptively significant at months 12, 18, and 24 in favor of WS 1442 for sudden cardiac death (Fig. 3). The results point to a potential antiarrhythmic and/or anti-ischemic effect already observed in animal models, where WS 1442 prevented reperfusion arrhythmias effectively.

Benefit-Risk Assessment of Crataegus Extract WS 1442: An Evidence-Based Review
https://pmc.ncbi.nlm.nih.gov/articles/PMC5772138/

In broader terms, Hawthorn may also be effective at quelling chronic systemic low-level inflammation. Particularly inflammation involving the Spike Protein’s preferred cytokines and pathways.

An in vitro study on mouse macrophage cell line showed that an aqueous extract of hawthorn fruit suppressed expression of inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 (Kim et al., 2011), which may be regulated by the nuclear factor (NF)-κB, a well-known mediator for its role in pro- and anti-inflammatory regulation and for controlling the expression of inflammatory genes including adhesion molecules, cytokines, and chemokines. Data from Crataegus aronia extracts showed inhibition of the nuclear accumulation of NF-κB and NLRP-3 protein levels and caspase-1 in HFD-induced aortic vascular inflammation in rats, thus suggesting inhibition of the NLRP3 inflammasome-mediated pathway (Shatoor and Al Humayed, 2019). The monocyte/macrophage is a major immunocyte involved in atherosclerosis, which scavenges modified LDLs and accelerates the local inflammatory response (Kao et al., 2005). One study reported that water extracts of C. pinnatifida inhibited NO production and inflammatory gene expression, including TNF-α, COX-2, IL-1β, and IL-6 in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells (Li and Wang, 2011). In addition, ethanol extracts of C. pinnatifida seeds elicit a potent NO and TNF-α inhibitory effect, hence regarded as a promising and reliable source of antioxidants and inhibitors of inflammation (Peng et al., 2016).

Roles and Mechanisms of Hawthorn and Its Extracts on Atherosclerosis: A Review
https://pmc.ncbi.nlm.nih.gov/articles/PMC7047282/

A word of caution. Hawthorn is not for everyone and should only be used under the guidance and care of your primary care provider. It can interact negatively with some medications. So, as with all medications and supplements, always consult your primary care provider before using.

Thank you, as always, for your readership, dialogue and support. I received a generous donation in the mail this week accompanied by a beautifully written Thank You card. I was deeply moved and humbled. Thank you. And thanks to all, always. Please have a blessed weekend.

One-Time Donation (Donor Decides Amount)
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00

Last week we discussed how the recent surge in cancers may be, at least in part, due to a clinical and most likely sub-clinical systemic inflammatory disease brought about by SARS-Cov-2 and its Spike Protein. Today I would like to discuss how this very same clinical and sub-clinical disease state may also be responsible for the recent surge in sudden cardiac deaths. Let’s start by recalling one fact about the heart’s electrical stability.

In many chronic diseases, the heart gradually becomes more electrically unstable before structural disease becomes clinically obvious.

Indeed, early in the pandemic it was thought that only the virus directly damaging the heart led to the increase in lethal arrhythmias. However, it was discovered that this was true for only a small minority of patients. Therefore, other mechanisms were needed to explain the increased presence of arrythmias. Enter inflammation, a suspect for which one can build an immense case against – especially when one considers which inflammatory cytokines the Spike Protein is most adept at increasing.

In the initial phases of the pandemic, it was thought that COVID-19-associated arrhythmias mostly resulted from disease-specific mechanisms, such as cardiac injury due to direct viral invasion, or electrophysiological effects of repurposed ‘off-label’ drugs, particularly antimalarials, azithromycin and protease inhibitors. However, it has become evident that direct virus-induced cardiac damage occurs in only a small minority of patients. Moreover, although the above mentioned drugs were progressively abandoned owing to a lack of efficacy, the risk of arrhythmia remained high.

On the basis of these observations, focus then shifted to the potential role of other arrhythmogenic factors, such as tissue hypoxia due to lung damage and the systemic high-grade inflammatory state. Indeed, it was demonstrated that both factors can induce cardiac injury, as reflected by an increase in troponin levels, and the rates and severity of this complication are similar in non-COVID-19 severe pneumonia or sepsis. Here, the contribution of inflammatory cytokines to cardiac injury may be particularly relevant. It has become apparent that several patients with COVID-19, as well as individuals with non-COVID-19 pneumonia, can develop life-threatening arrhythmic events, despite the absence of a severe respiratory impairment, when an intense systemic inflammatory activation was present4. In patients with COVID-19, increased levels of circulating proinflammatory cytokines directly correlated with increased troponin levels3. Moreover, in vitro treatment of cardiomyocytes with IL-6 and IL-1β resulted in disorganization of myofibrils, as well as reduced and erratic beating, similar to what was observed after infection of these cells with SARS-CoV-2 (ref.5). Thus, it is likely that cytokines also increase myocardial electric instability as a result of a direct cell injury, which indicates that the inherent arrhythmogenic effects of inflammatory cytokines are important drivers of COVID-19-associated arrhythmias, similar to what is observed in other inflammatory conditions. Indeed, it was reported that increased levels of IL-6 and IL-10 were predictive of the risk of atrial and ventricular arrhythmias in patients hospitalized with COVID-19 (ref.6).

Inflammatory cytokines and cardiac arrhythmias: the lesson from COVID-19
https://www.nature.com/articles/s41577-022-00714-3

I am proposing that continual exposure to the Spike Protein via reinfection, gene therapy and/or viral reservoirs may promote the same kind of arrhythmias – manifesting in some cases over a much longer period due to the possibility of resulting persistent sub-clinical inflammation. To understand how this may occur, let’s look at an enormous UK study examining the relationship between systemic inflammation and incident arrhythmias. The study included 478, 524 volunteer participants through the UK Biobank. What the study found is very insightful.

Compared with the 445,647 participants in the control group, the 32,877 participants in the incident arrhythmia group were more likely to be older, male, and less educated, and tended to have higher BMI, higher systolic blood pressure, a higher smoking rate, and a higher prevalence of comorbid diseases (Table 1). Considering the possible correlation between systemic inflammation levels and baseline characteristics, we have shown the baseline characteristics of patients for different levels of CRP (as an indicator of systemic inflammation). Participants with higher CRP levels were more likely to be older, less educated, and smokers, and tended to have a higher Townsend deprivation index, higher BMI, higher systolic and diastolic blood pressure, lower alcohol consumption, lower physical activity intensity, and higher prevalence of comorbid diseases (Additional file 1: Table S3).

Systemic inflammation indicators and risk of incident arrhythmias in 478,524 individuals: evidence from the UK Biobank cohort
https://link.springer.com/article/10.1186/s12916-023-02770-5

To the above participants in the incident arrhythmia group, one might add Spike Protein persistence as a “baseline characteristic.” This would then be the basis of a Spike-induced sub-clinical inflammatory state promoting arrhythmias.

Further evidence for a subclinical disease state arrhythmogenic cause is provided by the observation that the cytokines elevated by Spike Protein happen to be more “effective” at creating arrhythmias when their presence is cumulative.

It is important to note that in vivo, during inflammatory activation, all these cytokines are concomitantly released, and for this reason it is likely that their overall electrophysiological effects may be cumulative. In agreement, a recent simulation study incorporated part of the above-mentioned experimental data on TNF, IL-1, and IL-6 into a human cell model and confirmed that each cytokine leads to a significant prolongation of APD and QT interval, in the presence of increased transmural and regional repolarization heterogeneities. These changes were significantly enhanced when the effects of the 3 cytokines were analyzed in combination (Figure 1).40

Fir(e)ing the Rhythm: Inflammatory Cytokines and Cardiac Arrhythmias
https://www.jacc.org/doi/10.1016/j.jacbts.2022.12.004

Additionally, the pro-fibrotic effects of the Spike Protein may also impact over time in a sub-clinical state, resulting in arrhythmogenesis.

It is well established that cardiac fibrosis can significantly disturb electrical impulse propagation and generate re-entry circuits, thus contributing to the occurrence of both conduction defects and re-entrant VAs.72 A large number of experimental studies have implicated inflammatory cytokines, specifically TNF, IL-1, and IL-6 in the pathogenesis of cardiac fibrosis. As recently reviewed in an excellent paper by Frangogiannis,73 multiple mechanisms are involved, including direct activation of myofibroblast-driven extracellular matrix synthesis, and indirect effects mediated by macrophage recruitment, transforming growth factor-β up-regulation, and production of matrix-regulator molecules.

Fir(e)ing the Rhythm: Inflammatory Cytokines and Cardiac Arrhythmias
https://www.jacc.org/doi/10.1016/j.jacbts.2022.12.004

Why do we need to determine if there is a slow inflammatory fire burning in some percentage of those exposed to SARS-CoV-2 and/or its Spike Protein? Because of autopsy results reported in 2024. The authors of a study examined the skulls of patients who died of NON-COVID related causes – and found spike protein in 10 out of 34 samples.

We examined skulls of patients who died from non-COVID-19-related causes in 2021 and 2022 and identified spike protein in 10 out of 34 samples (Figures 1G and S1I; Table S2), indicating that spike protein can persist long after infection resolution, potentially contributing to long-term COVID-19 symptoms. Notably, a correlation has been observed between persistent circulating spike protein in plasma and post-acute sequelae of COVID-19.

Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19
https://www.sciencedirect.com/science/article/pii/S1931312824004384

Given the vast tropism of the Spike Protein, I am quite certain that it will be found persisting in far more places than just the skull. Thank you, as always, for your readership, dialogue and support. I cannot do this without you. Please have a blessed week.

One-Time Donation (Donor Decides Amount)
https://buy.stripe.com/6oUbJ0auFaWkcLs2ZXeUU00