John D. MacArthur

Lining the interior of the entire vascular system is the endothelium, which is composed of a single layer of endothelial cells. One of the largest organs in an adult body, if all the endothelium tissue were to be spread out, it would take up the area of eight tennis courts. As a selectively permeable layer between the blood and body, the endothelium regulates the transfer of chemicals and white blood cells according to where they are needed. Endothelial cells actively and reactively participate in immune and inflammatory reactions.¹

In the spring of 2020, researchers recognized that pre-existing endothelial dysfunction is a common underlying factor among people with an increased risk of severe coronavirus disease 2019 (COVID-19). Poor clinical outcomes and high mortality rates due to COVID-19 infections were seen in patients with underlying conditions in which endothelial dysfunction is a significant factor: hypertension, obesity, diabetes, kidney disease. A comprehensive evaluation of both clinical and preclinical evidence support “the hypothesis that the endothelium is a key target organ in COVID-19, providing a mechanistic rationale behind its systemic manifestations.”²

“Endothelium appears to be the battlefield of COVID-19.” The deaths of so many older adults could be caused by a common underlying circumstance: the progressive decline of endothelial function with age, further complicated by other coexisting comorbidities associated with endothelial dysfunction. “An effective endothelial dysfunction treatment might change the disease course.”³

“The vascular endothelium and the various manifestations of its dysfunction in the context of COVID-19 have been considered to be cardinal features.” These terms may be used interchangeably: endothelial dysfunction, endothelial activation, endothelial damage, and endothelial injury.⁴

Vascular biologist Dr. William Li compares the healthy endothelium to a freshly resurfaced ice hockey rink. “When the virus damages the inside of the blood vessel and shreds the lining, that’s like the ice after a hockey game… We found blood vessels are blocked and blood clots are forming because of that lining damage.” COVID-19 patients have both of these markers of endothelial dysfunction. Li’s team found nine times as many microthrombi (tiny blood clots) in the lung tissues of people who died of COVID-19 compared with those who died of influenza. Coronavirus-infected lungs also exhibited “severe endothelial injury.”⁵

By the spring of 2021, a wealth of studies indicated that COVID-19 patients with prior endothelial dysfunction are predisposed to vascular complications and develop a higher rate of severe disease outcomes.⁶

A review that summarized a large amount of scientific evidence found that endothelial dysfunction represents the common denominator of most clinical manifestations of COVID-19. This is supported by the strong interrelationship between inflammation, oxidative stress, and endothelial function.⁷

A comprehensive 2010 review (“Molecular mechanisms of fluoride toxicity”) provides information on how fluoride affects cells, with an emphasis on tissue-specific events in humans. “Endothelial dysfunction and vascular disorders have been associated with fluoride exposure in cell lines and in humans. The data suggest an important role played by factors related to oxidative stress and vascular inflammation.”⁸

New research has identified clusters of endothelial cells specialized to detect specific stimuli. A well-developed (but poorly understood) communication system processes endlessly arriving requests from these clusters of endothelial cells. A high density of interlinked connections integrates multiple lines of information and coordinates endothelial responses. This complex sensory and physiological control system regulates blood flow, blood pressure, blood clotting, inflammation, and response to disease – as well as the exchange of oxygen, nutrients, and waste products between circulating blood and tissue.^9,10

This new understanding suggests that if the endothelium is analogous to an ice rink, that ice is not simply a solid mass of frozen water. Below the surface are pathways of flowing water that connect and communicate with different regions of the ice. What’s more, if the endothelium is ice, then fluoride is salt.

In 2001, researchers at Johns Hopkins University School of Medicine “demonstrated that [sodium fluoride] causes dramatic endothelial cell barrier dysfunction, as evidenced by increases in macromolecule permeability.”¹¹ In 2006, they reported that sodium fluoride evokes time-dependent ERK activation that contributes to endothelial cell barrier disruption in pulmonary endothelial cells.¹²

The ERK (extracellular signal-regulated kinase) signaling pathway is essential for causing viral spread. ERK activation has been observed during infections with respiratory viruses. “Coronaviruses can also recruit this pathway to facilitate their replication and pathogenesis.”¹³

To help mitigate rapid disease progression and high mortality of COVID-19, what’s needed are “therapies directly and indirectly aimed to prevent endothelial dysfunction and/or improve endothelial function.”¹⁴

“It is apparent that fluorides have the ability to interfere with the functions of the brain and the body by direct and indirect means.”
– National Research Council¹⁵

Endothelin-1

A large body of evidence suggests that endothelin-1 (ET-1), a peptide secreted mainly from vascular endothelial cells, is a key player in endothelial dysfunction.¹⁶ ET-1 is a potent vasoconstrictor. Clinical and experimental data indicate that ET-1 is involved in the pathogenesis of viral and bacterial pneumonia.¹⁷

An August 2020 report (“The enigma of endothelium in COVID-19”) notes that circulating molecules such as ET-1 that signify endothelial dysfunction may appear as early biomarkers of viral infection and probable organ dysfunction.¹⁸ Increased circulating levels of ET-1 are an important pathological factor that can be therapeutically targeted in COVID-19.¹⁹

Increased plasma levels of ET-1 were observed in people with increasing concentrations of fluoride in their drinking water.²⁰ “Plasma ET-1 levels of rabbits increased significantly in fluorinated groups compared with those in the control group.” Excessive fluoride exposure leads to endothelial damage and thoracic aorta hardening.²¹

An epidemiological study showed that elevated plasma levels of ET-1 caused by fluoride lead to inflammation and endothelial activation connected with the incidence of adult hypertension.²²

Cellular Senescence

Senescent endothelial cells that have lost their ability to divide are a common mechanism in age-related diseases, including hypertension, dementia, diabetes, and cardiovascular disease. Although these “zombie cells don’t function properly, they’re not couch potatoes. They actively secrete chemicals that promote inflammation and damage neighboring cells.”²³

Infectious agents can cause pre-existing senescent cells to become even more inflammatory and destructive. Research suggests that senescence is a chronic health consequence of COVID-19. The elderly and patients with pre-existing cellular senescence-associated conditions are more susceptible to more severe cases of acute COVID-19 and/or prolonged effects after the initial acute infection.²⁴ A May 2021 review describes updated studies on the association between cellular senescence and COVID-19.²⁵

The number of senescence-positive cells in rat liver tissues increased with fluoride concentration.²⁶ Glycine alleviated sodium fluoride-induced cellular senescence in the porcine testicular Sertoli cell line.²⁷

During aging, the immune system loses its ability to mount an effective response against pathogens, which can increase disease susceptibility and limit the effectiveness of vaccinations. Termed “immunosenescence,” this decline in immune function affects innate and adaptive immunity and contributes to the morbidity and mortality of the elderly.²⁸

Cellular senescence, mitochondrial dysfunction, and telomere dysfunction are “pillars of aging” that can contribute to age-related disease and dysfunction. The introduction of a viral infection can trigger a stress response, which can interfere with telomeric maintenance, causing telomere shortening. op. cit.²⁴ Telomeres are structures made from DNA sequences and proteins found at the ends of chromosomes. They cap and protect the end of a chromosome (like the end of a shoelace).

A report that summarized theoretical and experimental data concluded that “telomere shortening is a cellular senescence biomarker of choice.” Telomeres are considered by most scientists to be indicative of aging in addition to being a potential factor in determining life expectancy.²⁹

A review of the interconnection between immunosenescence and COVID-19 reported that patients who possessed shorter telomeres have an elevated risk of developing severe COVID-19 pathologies.³⁰ A July 2022 cohort study of 435,046 UK Biobank participants found that longer telomere length is a protective factor against cognitive impairment, Alzheimer’s disease and related dementias.³¹

SIRT1

“Studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders.”³²

Silent information regulator 1 (SIRT1) is a ubiquitously expressed protein and has an intricate role in the pathology, progression, and treatment of several diseases.³³ Findings of a study suggest that SIRT1 “may ameliorate lung inflammation, inhibit alveolar epithelial cell senescence and delay the progression of COPD.”³⁴

SIRT1 can regulate immune response and has been reported to play key regulatory role in senescence and neurodegenerative diseases. Fluoride exposure downregulates SIRT1.³⁵

A study found that exposure to the inhaled fluorinated anesthetic sevoflurane significantly suppressed the expression of SIRT1. Also, that pretreatment with resveratrol ameliorated sevoflurane-induced SIRT1 inhibition.³⁶

Fluorinated Drugs

5-fluorouracil is a fluorinated drug that “causes endothelial cell senescence and dysfunction, which may contribute to its cardiovascular side effects.”³⁷

Following application of 5-fluorouracil, plasma levels of fluoride were 5 to 33 times higher.³⁸

5-fluorouracil treatment “induced ultrastructural changes in the endothelium of various organs,” including substantial effects on the cardiovascular system. A study of the effects of 5-fluorouracil on morphology in endothelial cells and cardiomyocytes (heart-muscle cells primarily involved in the contractile function) found induction of a senescent phenotype on both cell types.³⁹

A study that explored fluoride’s mechanism of apoptosis found that sodium fluoride (NaF) not only inhibited cardiomyocyte proliferation, but also induced apoptosis and morphological damage. With increasing NaF concentrations, early apoptosis of cardiomyocytes was increased while the mitochondrial membrane potential was decreased.⁴⁰

Fluoride has been considered as a risk factor of cardiovascular disease due to its endothelial toxicology. A study “confirmed that fluoride exposure induced the apoptosis of endothelial cells both in established rats model and cultured human umbilical vein endothelial cells.”⁴¹

Another fluorinated drug that raises blood levels of fluoride is the inhaled anesthetic sevoflurane used in mechanical ventilation and sedation.

“Sevoflurane administration can result in increased serum inorganic fluoride ion concentrations.” Three of 24 patients exposed to sevoflurane had fluoride levels over 50 micro mol/L, “the ‘toxic’ level often cited for inorganic fluoride.” One of these patients had a serum inorganic fluoride ion level over 50 micro mol/L at 12 hours after sevoflurane, and an additional patient had fluoride levels over 33 micro mol/L for up to 24 hours after sevoflurane discontinuation.⁴²

“The fluoride ion is the toxicologically active agent.”
– Toxicological Profile for Fluorides, Public Health Service⁴³

A review of 41 randomized controlled trials in human patients found that peak plasma fluoride and fluoride levels measured at 24 hours were higher with sevoflurane compared with other inhaled anesthetics.⁴⁴

A 2015 study (“Sevoflurane and isoflurane induce structural changes in brain vascular endothelial cells and increase blood–brain barrier permeability”) found a “marked flattening” of endothelial cells in the brains of sevoflurane-treated rats.⁴⁵

Note: Fluorinated drugs reveal mechanisms of fluoride that may also apply to chronic exposure to low levels of fluoride, especially in sensitive subpopulations, including people with a genetic susceptibility to fluoride’s adverse effects.

Delirium

Delirium is a serious change in brain function that affects up to 64% of older medical patients and up to 50% of older surgical patients. It can manifest as sudden confusion, agitation, memory loss or hallucinations and delusions. Estimated to cost the U.S. health care system as much as $182 billion annually, delirium is linked with longer hospital stays, complications, and increased risks of dementia and death.⁴⁶

“Surgical patients who suffer one episode of delirium have 12 times the likelihood of developing an Alzheimer’s or related dementia diagnoses within a year compared to similar surgical patients who do not experience delirium.”⁴⁷

Emergence delirium (ED) refers to a variety of behavioral disturbances commonly seen in children following emergence from anesthesia. Inhalational anesthesia with sevoflurane, the most common pediatric anesthetic technique, is associated with the highest incidence of ED. A randomized-controlled trial found ED incidence was 38.3% with sevoflurane compared to 14.9% with a propofol-based intravenous anesthesia.⁴⁸

A similarly significant result was found in elderly patients. The incidence of postoperative delirium from sevoflurane was nearly four times higher than from a propofol-based intravenous anesthesia.⁴⁹

“Researchers from King’s College London have shown that when brain cells are directly exposed to blood taken from COVID-19 patients with delirium, there is an increase in cell death and a decrease in the generation of new brain cells…indicating that, in these patients, the COVID-19 infection had impacted the brain.”⁵⁰

Interleukin-6

A study found that the fluorinated anesthetic isoflurane, one of the most commonly used inhalation anesthetics, can increase the level of interleukin-6 and other proinflammatory cytokines, which may cause neuroinflammation, leading to promotion of Alzheimer’s disease neuropathogenesis.⁵¹

Interleukin-6 (IL-6) is an important marker of cellular senescence and COVID-19.⁵² “IL-6 causes endothelial barrier dysfunction via the protein kinase C pathway.”⁵³

A July 2021 analysis of 27 randomized trials involving nearly 11,000 hospitalized COVID-19 patients found that administering a drug that blocked the effects of IL-6 prevented progression to severe illness, reduced the need for mechanical ventilation and the risk of death.⁵⁴

Fluoride exposure has been shown to mediate the expression of over 1,000 genes in humans and was found to upregulate specifically the expression of IL-6.⁵⁵ Sodium fluoride induced IL-6 in human epithelial lung cells.⁵⁶

Sevoflurane has also been shown to elevate the serum level of IL-6 in mice.⁵⁷ Fluoride significantly increased IL-6 protein expression in the cortex and hippocampus of rats.⁵⁸ In fluoride-exposed rats, IL-6 increased more than 2.5 fold in plasma.⁵⁹

Mitochondrial Dysfunction

Mitochondria are energy-producing, membrane-bound organelles that produce most biochemical reactions within cells. Mitochondria serve a variety of purposes, including regulating metabolism and apoptosis. Age-related mitochondrial dysfunction is a key factor in COVID-19. Given the importance of mitochondria in immune functions, a high mitochondrial fitness should be considered as protective factors for viral infections, including COVID-19. “This assumption is corroborated by reduced mitochondrial fitness in many established risk factors of COVID-19, like age, various chronic diseases or obesity.”⁶⁰

An April 2022 review of the mechanism of cytotoxicity related to mitochondrial dysfunction found that numerous studies in different model systems reported that mitochondrial dysfunction is a shared feature of fluorosis. “Fluoride invades into cells and mainly damages mitochondria… Long-term exposure of fluoride irreversibly damages the integrity of the mitochondrial membrane, resulting in mitochondrial dysfunction.”⁶¹ An earlier report reviewed “fluoride-induced mitochondrial alterations on soft and hard tissues, including liver, reproductive organs, heart, brain, lung, kidney, bone, and tooth.”⁶²

“In vitro studies revealed that fluoride alters mitochondrial homeostasis… Even a low dose of fluoride exposure induces ROS synthesis, which causes further damage to the mitochondrial membrane potential.”⁶³

A February 2020 study concluded that excessive fluoride intake induced “mitochondrial respiratory chain damage and mitochondrial fusion disorder.”⁶⁴

The protein mitofusin-1 (MFN1) is found on the outer membranes of mitochondria. Increasing levels of MFN1 might be used to treat patients with neurodegenerative diseases.⁶⁵

In the cortices of the brains and the renal tissues of rats with chronic fluorosis, the level of MFN1 protein was clearly reduced. These findings indicate that chronic fluorosis can lead to the abnormal mitochondrial dynamics.^66,67

Mitochondria contain a form of mitochondrial DNA (mtDNA) that is known to have high rates of mutations, many of which are linked to diseases such as cancer, diabetes, and several neurodegenerative disorders.

Several studies have linked fluoride exposure to mitochondrial dysfunction, including alterations in mitochondrial DNA. Circulating mitochondrial DNA content is negatively related to low-to-moderate concentrations of water fluoride, to urinary fluoride levels, and to dental fluorosis prevalence. Human fetal brain samples in areas with fluorosis have a significantly lower volume and density of mitochondria compared to those that have not been exposed. A study of Chinese children illustrated how low-to-moderate water fluoride and urinary fluoride levels show an inverse association with mitochondrial DNA levels, a marker of mitochondrial dysfunction.⁶⁸

“Fluoride ions are highly reactive.” To investigate the molecular bases of dental fluorosis (visually recognizable tooth enamel defects), researchers analyzed the effects of fluoride exposure in enamel cells. They found that “fluoride negatively affected mitochondrial respiration, elicited mitochondrial membrane depolarization, and disrupted mitochondrial morphology.”⁶⁹

Endothelial Dysfunction in Underlying Conditions for COVID-19

Among COVID-19 hospitalizations of 906,849 U.S. adults, researchers in early 2021 estimated that 30% were attributable to obesity, 26% to hypertension, and 21% to diabetes.⁷⁰

“The meta-inflammation in obesity intersects with and exacerbates underlying pathogenetic mechanisms in COVID-19” through mechanisms and factors that include endothelial dysfunction, chronic inflammation and oxidative stress. The clinical presentation of COVID-19 may be worse in susceptible patients with pre-existing endothelial dysfunction.⁷¹

“Endothelial dysfunction should be considered a central focus for the treatment of hypertension.”⁷²

Data shows that endothelial dysfunction of the microvasculature precedes the development of type 2 diabetes mellitus.⁷³

A November 2022 analysis of 64,246 COVID-19 cases during 4 waves of the pandemic in New York City found that pre-existing chronic kidney disease was one of the most consistent clinical predictors for the risk of severe COVID-19.⁷⁴ The initiation and the progression of endothelial dysfunction is simultaneously a cause and a consequence of chronic kidney disease.⁷⁵

A September 2021 systematic review found a significantly higher prevalence of altered thyroid hormones and hypothyroidism in COVID-19 patients, as compared to control groups.⁷⁶ A meta-analysis of 10 studies with 760 subjects demonstrated that subclinical hypothyroidism is associated with endothelial dysfunction.⁷⁷

An upcoming Townsend e-Letter will explore the fluoride factors in these underlying conditions for COVID-19.

Polyphenols Reduce Endothelial Dysfunction and Protect Against COVID-19 and Fluoride Toxicity

Improving or maintaining a normal endothelial function by well-established lifestyle measures (i.e. keeping a normal weight, regular physical activity, abstaining from smoking, and consuming a healthy and nutritious diet) may be helpful to reduce the risk of COVID-19. Specific supplemental interventions that reduce endothelial dysfunction should also be considered.⁷⁸

Polyphenols are a category of compounds naturally found in many plant foods. Polyphenols represent a valuable therapeutic strategy for the management of COVID-19. From available evidence documented in an August 2020 review, “polyphenols are endowed with multifaceted beneficial properties. Their antiviral, antioxidant, anti-inflammatory, antiobesogenic, antidiabetic, antithrombotic, and prebiotic effects can be put in use to combat COVID-19.”⁷⁹

Quercetin, curcumin, and resveratrol are three polyphenols shown to protect against COVID-19. Evidence suggests that this is aided by their ability to also protect against fluoride’s toxic effects.

Quercetin

Amongst natural molecules for COVID-19 treatment, quercetin is currently considered one of the most promising. A September 2022 review found that quercetin is a “potent immunomodulatory molecule due to its direct modulatory effects on several immune cells, cytokines, and other immune molecules.”⁸⁰

“Quercetin represents a promising natural compound that appears to satisfy all the requirements to develop a nutraceutical against endothelial dysfunction.” A growing body of evidence suggests quercetin could lower the risk of ischemic heart disease “by mitigating endothelial dysfunction and its risk factors, such as hypertension, atherosclerosis, accumulation of senescent endothelial cells.”⁸¹ The effectiveness of quercetin in treating cardioprotective and neuroprotective diseases has been remarkably covered by researchers.⁸²

Quercetin inhibits pro-inflammatory signals from IL-6 that promote acute respiratory distress syndrome in patients with COVID-19.⁸³

Rat studies conclusively proved quercetin’s neuroprotective ability against fluoride-induced toxicity.⁸⁴ Quercetin protects the brain from sodium fluoride-induced oxidative stress, neural damage, and behavioral alterations.⁸⁵

Rat studies by Nabavi et al. revealed a potent protective potential of quercetin against sodium fluoride-induced toxicity in the brain and heart.^86,87 Another study demonstrated that quercetin and curcumin exert impressive protection against thyroid dysfunction in rats induced by fluoride in their drinking water.⁸⁸

Note: Rodent studies with higher doses of fluoride are relevant to humans. Researchers at the Forsyth Institute in Massachusetts (a fluoride research center for the past century) found that rodents more efficiently clear fluoride from their bodies, so a higher fluoride dose is required to cause fluorosis compared with a human.⁸⁹

An August 2022 study (“Cellular senescence: a key therapeutic target in aging and diseases”) demonstrated the feasibility of eliminating senescent cells by using the combination of dasatinib plus quercetin.⁹⁰ Senolytics are a class of drugs that selectively clear senescent cells.

Curcumin

A yellow-pigment found in the popular Indian spice turmeric, curcumin was shown to mitigate hypertension, endothelial dysfunction, and oxidative stress in rats with chronic exposure to lead and cadmium.⁹¹ Findings from a 2016 study suggest that supplementation with 200 mg per day of curcumin enhances endothelial function.⁹²

For management or treatment of COVID-19, curcumin should be used for several reasons: it is relatively safe; it shows broad-spectrum antiviral activity; it exerts immunomodulatory activity by blocking NF-κB and IL-6 driven inflammatory responses.⁹³

Curcumin effectively and efficiently mitigates the genotoxic effects of the two well known water contaminants, arsenic and fluoride.⁹⁴

“Pre-administration of curcumin prevents neonatal sevoflurane exposure-induced neurobehavioral abnormalities in mice.”⁹⁵ Results of a May 2020 study showed the neuroprotective effects of curcumin on behavior, neurotransmitter levels, and histological changes induced by fluoride in the hippocampus of developing rat pups.⁹⁶

Animals that were pretreated with curcumin had a significant reduction in the level of malondialdehyde, a marker for oxidative stress that was increased in sodium-fluoride-treated rats.⁹⁷ Curcumin treatment also showed significant protective effects against sodium fluoride-induced toxicity in rat kidneys.⁹⁸ Sodium fluoride affected both the function and structure of the thyroid gland in rats, while curcumin was protective against these toxic effects.⁹⁹

Resveratrol

A natural polyphenol that has been detected in more than 70 plant species, resveratrol can interfere with viral replication through inhibition of viral gene expression and through downregulation of various cellular signaling pathways. Resveratrol inhibits SARS-CoV-2 replication in primary bronchial epithelial cell cultures and downregulates several pathogenetic mechanisms involved in COVID-19 severity.¹⁰¹

“The protective effect of resveratrol results from its capability to reduce fluorine-induced oxidative stress and endothelial tissue damage.”¹⁰⁰

Resveratrol has the ability to protect mitochondrial function, as shown in a study that provided “in vivo and in vitro evidence demonstrating that impaired mitochondrial biogenesis… contributes to developmental neurotoxicity induced by chronic and long-term fluoride exposure.” Resveratrol promotes mitochondrial biogenesis and mitochondrial function by activating a SIRT1-dependent signaling pathway, “thus counteracting developmental neurotoxic effects caused by fluoride.”¹⁰²

Extensively studied in regulating aging and age-related diseases, sirtuins are considered to have anti-inflammatory properties due to their regulatory effects on transcription factors. SIRT1 can reduce pro-inflammatory cytokines by inhibiting the activity of NF-κB.¹⁰³ “NF-κB is essential for virus replication… that culminates in the pathology associated with COVID-19.”¹⁰⁴

An April 2021 study found that pretreatment with resveratrol ameliorated sevoflurane-induced SIRT1 inhibition and cognitive impairment in developing mice. Furthermore, the levels of IL-6 were markedly increased after sevoflurane exposure.³⁶

Repeated sevoflurane exposures induced long-term cognitive impairment in mice and reduced neuronal numbers by increasing levels of IL-6 and NF-κB pathway-related proteins.¹⁰⁵

“Sodium fluoride induces renal inflammatory responses by activating NF-κB signaling pathway and reducing anti-inflammatory cytokine expression in mice.”¹⁰⁶

“Several in vitro and in vivo studies have shown that fluoride may play an indirect role in the regulation of the NF-κB pathway.”¹⁰⁷

In his comprehensive March 2022 review (“The potential of dietary bioactive compounds against SARS-CoV-2 and COVID-19-induced endothelial dysfunction”), Jack Losso, a professor at LSU’s School of Nutrition and Food Sciences, begins: “COVID-19 is an endothelial disease. All the major comorbidities that increase the risk for severe SARS-CoV-2 infection and severe COVID-19 including old age, obesity, diabetes, hypertension, respiratory disease, compromised immune system, coronary artery disease or heart failure are associated with dysfunctional endothelium.”¹⁰⁸

He concludes: “Preventing and reversing endothelial dysfunction appear to be feasible… Well-designed healthy diets can help prevent endothelium dysfunction. Current and future efforts in food research and product development should consider vascular dysfunction as an important target in healthy eating because improving vascular function helps prevent endothelial dysfunction, metabolic syndrome, and reduces the severity of SARS-CoV-2 infection… Other viruses worse than SARS-CoV-2 and COVID-19 may be awaiting in nature.”¹⁰⁸

“Vascular Fluorosis” will be explored in a future Townsend e-Letter.

Published April 8, 2023

REFERENCES:

1. Toran M. VIDEO: What are Endothelial Cells? Study.com (2023); Galley H, Webster N. Physiology of the endothelium. British Journal of Anaesthesia. 2004.

2. Sardu C, et al. Hypertension, thrombosis, kidney failure, and diabetes: Is COVID-19 an endothelial disease? A comprehensive evaluation of clinical and basic evidence. Journal of Clinical Medicine. May 2020.

3. Ghirga G. Pre-existing endothelial dysfunction: a unifying hypothesis for the burden of severe SARS-CoV-2. British Medical Journal. Rapid Response. May 7, 2020.

4. Zhang J, et al. Endothelial dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy. Reviews in Cardiovascular Medicine. September 2020.

5. Stone W. Clots, strokes and rashes: Is COVID a disease of the blood vessels? Kaiser Health News. Nov. 13, 2020.

6. Maruhashi T, Higashi Y. Pathophysiological association of endothelial dysfunction with fatal outcome in COVID-19. International Journal of Molecular Sciences. May 2021.

7. Ambrosino P. et al. Endothelial dysfunction in COVID-19: A unifying mechanism and a potential therapeutic target. Biomedicines. April 2022.

8. Barbier O. et al. Molecular mechanisms of fluoride toxicity. Chemico-Biological Interactions. 2010.

9. Lee MD, et al. Small-world connectivity dictates collective endothelial cell signaling. Proceedings of the National Academy of Sciences. April 2022.

10. Gallagher P. Study reveals how blood vessels use “short cuts” to control the cardiovascular system. University of Strathclyde. News Release. May 4, 2022.

11. Wang P, et al. Mechanisms of sodium fluoride-induced endothelial cell barrier dysfunction: role of MLC phosphorylation. American Journal of Physiology. 2001.

12. Bogatcheva N, et al. Mechanism of fluoride-induced MAP kinase activation in pulmonary artery endothelial cells. American Journal of Physiology. 2006.

13. Hemmat N, et al. The roles of signaling pathways in SARS-CoV-2 infection; lessons learned from SARS-CoV and MERS-CoV. Archives of  Virology. January 2021.

14. Deng H, et al. Endothelial dysfunction and SARS-CoV-2 infection: Association and therapeutic strategies. Pathogens. May 2021.

15. National Research Council. 2006. Fluoride in Drinking Water: A Scientific Review of EPA’s Standards. Washington, DC: The National Academies Press. Neurotoxicity and Neurobehavioral Effects. Page 222.

16. Iglarz M, Clozel M. Mechanisms of ET-1-induced endothelial dysfunction. Journal of Cardiovascular Pharmacology. 2007.

17. Freeman BD, et al. Endothelin-1 and its role in the pathogenesis of infectious diseases. Life Sciences. 2014.

18. Kaur S, et al. The enigma of endothelium in COVID-19. Frontiers of Physiology. August 2020.

19. Khodabakhsh P, et al. Vasoactive peptides: Their role in COVID-19 pathogenesis and potential use as biomarkers and therapeutic targets. Archives of Medical Research. June 2021.

20. Sun L, et al. An assessment of the relationship between excess fluoride intake from drinking water and essential hypertension in adults residing in fluoride endemic areas. Science of Total Environment. 2013.

21. Sun L, et al. Mechanisms underlying endothelin-1 level elevations caused by excessive fluoride exposure. Cellular Physiology and Biochemistry. 2016.

22. Wei W, et al. The pathogenesis of endemic fluorosis: Research progress in the last 5 years. Journal of Cellular and Molecular Medicine. 2019.

23. Jones A. Researchers uncover new pathway for accumulation of age-promoting ‘zombie cells.’ University of Pittsburgh. News Release. June 30, 2022.

24. Gerdes E, et al. Role of senescence in the chronic health consequences of COVID-19. Translational Research. October 2021.

25. Mohiuddin M, Kasahara K. The emerging role of cellular senescence in complications of COVID-19. Cancer Treatment and Research Communications. May 2021.

26. Wu CX, et al. Fluoride induced down-regulation of IKBKG Gene expression inhibits hepatocytes senescence. Journal of Trace Elements in Medicine and Biology. January 2022.

27. Liu Y, et al. Glycine alleviates fluoride-induced oxidative stress, apoptosis and senescence in a porcine testicular Sertoli cell line. Reproduction in Domestic Animals. June 2021.

28. Yousefzadeh M, et al. An aged immune system drives senescence and ageing of solid organs. Nature. June 2021.

29. Bernadotte A, et al. Markers of cellular senescence. Telomere shortening as a marker of cellular senescence. Aging. 2016.

30. Lynch S, et al. Role of senescence and aging in SARS-CoV-2 infection and COVID-19 disease. Cells. December 2021.v

31. Liu R, et al. Mid-life leukocyte telomere length and dementia risk: a prospective cohort study of 435,046 UK Biobank participants. (Preprint). medRxiv. July 2022.

32. Amano H, et al. Telomere dysfunction induces sirtuin repression that drives telomere-dependent disease. Cell Metabolism. 2019.

33. Singh V, Ubaid S. Role of silent information regulator 1 (SIRT1) in regulating oxidative stress and inflammation. Inflammation. October 2020.

34. Yuan D, et al. Senescence associated long non-coding RNA 1 regulates cigarette smoke-induced senescence of type II alveolar epithelial cells through sirtuin-1 signaling. The Journal of International Medical Research. February 2021.

35. Yu Y, et al. Fluoride exposure suppresses proliferation and enhances endoplasmic reticulum stress and apoptosis pathways in hepatocytes by downregulating sirtuin-1. BioMed Research International. 21 August 2022.

36. Tang X, et al. Resveratrol ameliorates sevoflurane-induced cognitive impairment by activating the SIRT1/NF-κB pathway in neonatal mice. Journal of Nutritional Biochemistry. April 2021.

37. Altieri P, et al. 5-fluorouracil causes endothelial cell senescence: Potential protective role of glucagon-like peptide 1. British Journal of Pharmacology. 2017.

38. Hull WE, et al. Metabolites of 5-fluorouracil in plasma and urine… Cancer Research. 1988. p. 1686.

39. Focaccetti C, et al. Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PLoS One. 2015.

40. Yan X, et al. Fluoride induces apoptosis in H9c2 cardiomyocytes via the mitochondrial pathway. Chemosphere. 2017.

41. Jiang Y, et al. Upregulation of miR-200c-3p induced by NaF promotes endothelial apoptosis by activating Fas pathway. Environmental Pollution. November 2020.

42. Goldberg M, et al. Sevoflurane versus isoflurane for maintenance of anesthesia: Are serum inorganic fluoride ion concentrations of concern? Anesthesia & Analgesia. 1996.

43. Public Health Service. Agency for Toxic Substances and Disease Registry. Toxicological profile for fluorides, hydrogen fluoride, and fluorine. 2003. Health Effects. Page 29.

44. Sondekoppam R, et al. The impact of sevoflurane anesthesia on postoperative renal function: a systematic review and meta-analysis of randomized-controlled trials. Canadian Journal of Anaesthesia. November 2020.

45. Acharya N, et al. Sevoflurane and isoflurane induce structural changes in brain vascular endothelial cells and increase blood–brain barrier permeability: Possible link to postoperative delirium and cognitive decline. Brain Research. 2015.

46. Meck C. Researchers develop scoring tool to measure severity of delirium. Beth Israel Deaconess Medical Center. News Release. March 31, 2022.

47. Regenstrief Institute. Research team awarded more than $10 million to improve cognitive recovery of post-operative delirium survivors. News Release. August 16, 2022.

48. Chandler J, et al. Emergence delirium in children: A randomized trial to compare total intravenous anesthesia with propofol and remifentanil to inhalational sevoflurane anesthesia. Pediatric Anesthesia. 2013

49. Ishii K, et al. Total intravenous anesthesia with propofol is associated with a lower rate of postoperative delirium in comparison with sevoflurane anesthesia in elderly patients. Journal of Clinical Anesthesia. 2016.

50. Lewis R. Interleukin-6 antagonists improve outcomes in hospitalised COVID-19 patients. King’s College London. News Release. July 6, 2021.

51. Wu X, et al. The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-α, IL-6, and IL-1β. Neurobiology of Aging. 2012.

52. Hariharan A, et. al. The role and therapeutic potential of NF-kappa-B pathway in severe COVID-19 patients. Inflammopharmacology. February 2021.

53. Desai TR, et al. Interleukin-6 causes endothelial barrier dysfunction via the protein kinase C pathway. Journal of Surgical Research. 2002.

54. Lewis R. Interleukin-6 antagonists improve outcomes in hospitalized COVID-19 patients. King’s College London. News Release. July 6, 2021.

55. Waugh D. The contribution of fluoride to the pathogenesis of eye diseases: Molecular mechanisms and implications for public health. International Journal of Environmental Research and Public Health. 2019.

56. Refsnes M, et al. Fluoride-induced interleukin-6 and interleukin-8 synthesis in human epithelial lung cells. Human Experimental Toxicology. 1999.

57. Li R, et al. Distinct effects of general anesthetics on lung metastasis mediated by IL-6/JAK/STAT3 pathway in mouse models. Nature Communications. January 2020.

58. Yan N, et al. Fluoride-induced neuron apoptosis and expressions of inflammatory factors by activating microglia in rat brain. Molecular Neurobiology. 2016.

59. Afolabi O, et al. Oxidative indices correlate with dyslipidemia and pro-inflammatory cytokine levels in fluoride-exposed rats. Archives of Industrial Hygiene and Toxicology. 2013.

60. Burtscher J, et al. The central role of mitochondrial fitness on antiviral defenses: An advocacy for physical activity during the COVID-19 pandemic. Redox Biology. July 2021.

61. Wei M, et al. Effect of fluoride on cytotoxicity involved in mitochondrial dysfunction: A review of mechanism. Frontiers in Veterinary Ccience. April 2022.

62. Avila-Rojas S, et al. Effects of fluoride exposure on mitochondrial function: Energy metabolism, dynamics, biogenesis and mitophagy. Environmental Toxicology and Pharmacology. August 2022.

63. Struzycka I, et al. Assessing fluorosis incidence in areas with low fluoride content in the drinking water. International Journal of Environmental Research and Public Health. June 2022.

64. Wang H, et al. Mitochondrial respiratory chain damage and mitochondrial fusion disorder are involved in liver dysfunction of fluoride-induced mice. Chemosphere. February 2020.

65. Engle J. Study: Protein key to Charcot-Marie-Tooth, other nerve diseases. Cedars-Sinai Medical Center. News Release. April 4, 2019.

66. Qin S, et al. The decreased expression of mitofusin-1 and increased fission-1 together with alterations in mitochondrial morphology in the kidney of rats with chronic fluorosis may involve elevated oxidative stress. Journal of Trace Elements in Medicine and Biology. 2014.

67. Lou D, et al. The influence of chronic fluorosis on mitochondrial dynamics morphology and distribution in cortical neurons of the rat brain. Archives of Toxicology. 2012.

68. Adkins E, Brunst K. Impacts of fluoride neurotoxicity and mitochondrial dysfunction on cognition and mental health: A literature review. International Journal of Environmental Research and Public Health. December 2021.

69. Aulestia F, et al. Fluoride exposure alters Ca2+ signaling and mitochondrial function in enamel cells. Science Signaling. February 2020.

70. Jenkins A. Study estimates two-thirds of COVID-19 hospitalizations due to four conditions. Tufts University. News Release. February 25, 2021.

71. Dalamaga M, et al. Understanding the co-epidemic of obesity and COVID-19: Current evidence, comparison with previous epidemics, mechanisms, and preventive and therapeutic perspectives. Current Obesity Reports. April 2021.

72. Maiuolo J, et al. “The contribution of gut microbiota and endothelial dysfunction in the development of arterial hypertension in animal models and in humans. International Journal of Molecular Ssciences. April 2022.

73. Hahad O, et al. Endothelial function assessed by digital volume plethysmography predicts the development and progression of type 2 diabetes mellitus. Journal of the American Heart Association. 2019.

74. Feheley C. Did having kidney disease and other conditions affect COVID-19 outcomes in different waves of the pandemic?  American Society of Nephrology. News Release. November 5, 2022.

75. Lousa I, et al. New potential biomarkers for chronic kidney disease management-A review of the literature. International Journal of Molecular Ssciences. 2020 Dec.

76. Malik J, et al. Association of hypothyroidism with acute COVID-19: A systematic review. Expert Review of Endocrinology & Metabolism. September 2021.

77. Gong N, et al. Endothelial function in patients with subclinical hypothyroidism: A meta-analysis. Hormone and Metabolic Research. 2019.

78. Nagele M, et al. Endothelial dysfunction in COVID-19: Current findings and therapeutic implications. Atherosclerosis. December 2020.

79. Levy E, et al. Can phytotherapy with polyphenols serve as a powerful approach for the prevention and therapy tool of novel coronavirus disease 2019 (COVID-19)? American Journal of Physiology. Endocrinology and Metabolism. August 2020.

80. Gasmi A, et al. Quercetin in the prevention and treatment of coronavirus infections: a focus on SARS-CoV-2. Pharmaceuticals (Basel, Switzerland). August 2022.

81. Dagher O, et al. Therapeutic potential of quercetin to alleviate endothelial dysfunction in age-related cardiovascular diseases. Frontiers in Cardiovascular Medicine. March 2021.

82. Bhat I, Bhar R. Quercetin: A bioactive compound imparting cardiovascular and neuroprotective benefits. Biology (Basel). June 2021.

83. Manjunath S, Thimmulappa R. Antiviral, immunomodulatory, and anticoagulant effects of quercetin and its derivatives: Potential role in prevention and management of COVID-19. Journal of Pharmaceutical Analysis. February 2022.

84. Mesram N, et al. Quercetin treatment against NaF induced oxidative stress related neuronal and learning changes in developing rats. Journal of King of Saudia University – Science. 2017.

85. Nageshwar M, et al. Quercetin ameliorates oxidative stress neural damage of brain and behavioral impairment of rat with fluoride exposure. International Journal of Pharmaceutical Sciences and Research. 2018.

86. Nabavi S, et al. Mitigating role of quercetin against sodium fluoride-induced oxidative stress in the rat brain. Pharmaceutical Biology. 2012.

87. Nabavi S, et al. Protective effect of quercetin against sodium fluoride induced oxidative stress in rat’s heart. Food & Function. 2012.

88. Nabavi S, et al. Protective effect of curcumin and quercetin on thyroid function in NaF-intoxicated rats. Fluoride. 2011.

89. Sharma R, et al. Fluoride induces endoplasmic reticulum stress and inhibits protein synthesis and secretion. Environmental Health Perspectives. 2008.

90. Zhang L, et al. Cellular senescence: a key therapeutic target in aging and diseases. The Journal of Clinical Investigation. August 2022.

91. Tubsakul A, et al. “Curcumin mitigates hypertension, endothelial dysfunction and oxidative stress in rats with chronic exposure to lead and cadmium. The Tohoku Journal of Experimental Medicine. January 2021.

92. Oliver J, et al. Novel form of curcumin improves endothelial function in young, healthy individuals. Journal of Nutrition and Metabolism. 2016.

93. Thimmulappa R, et al. Antiviral and immunomodulatory activity of curcumin: A case for prophylactic therapy for COVID-19. Heliyon. February 2021.

94. Tiwari H, Rao M. Curcumin supplementation protects from genotoxic effects of arsenic and fluoride. Food and Chemical Toxicology. 2010.

95. Ji M, et al. Pre-administration of curcumin prevents neonatal sevoflurane exposure-induced neurobehavioral abnormalities in mice. Neurotoxicology. 2015.

96. Kumar N, et al. Protective effect of curcumin on hippocampal and behavior changes in rats exposed to fluoride during pre- and post-natal period. Basic and Clinical Neuroscience. May 2020.

97. Nabavi S, et al. Cytoprotective effects of curcumin on sodium fluoride-induced intoxication in rat erythrocytes. Bulletin of Environmental Contamination and Toxicology. 2012.

98. Nabavi S, et al. Protective effects of curcumin against sodium fluoride-induced toxicity in rat kidneys. Biological Trace Element Research. 2011.

99. Abdelaleem M, et al. Possible protective effect of curcumin on the thyroid gland changes induced by sodium fluoride in albino rats: light and electron microscopic study. Endocrine Regulations. 2018.

100. Rossi G, et al. Can resveratrol-inhaled formulations be considered potential adjunct treatments for COVID-19? Frontiers in Immunology. 2021 May.

101. Bulduk M, et al. The effect of resveratrol therapy on the vascular responses caused by chronic fluorosis. Fluoride. January 2020.

102. Zhao Q, et al. SIRT1-dependent mitochondrial biogenesis supports therapeutic effects of resveratrol against neurodevelopment damage by fluoride. Theranostics. March 2020.

103. Pan Z, et al. Oxidative stress and inflammation regulation of sirtuins: New insights into common oral diseases. Frontiers in Physiology. August 2022.

104. Nilsson-Payant, et al. The NF-κB transcriptional footprint is essential for SARS-CoV-2 replication. Journal of Virology. December 2021.

105. Zhang Qi, et al. IL-17A deletion reduces sevoflurane-induced neurocognitive impairment in neonatal mice by inhibiting NF-κB signaling pathway. Bioengineered. January 2022.

106. Luo Q, et al. Sodium fluoride induces renal inflammatory responses by activating NF-κB signaling pathway and reducing anti-inflammatory cytokine expression in mice. Oncotarget. 2017.

107. Zwierello, et al. Fluoride in the central nervous system and its potential influence on the development and invasiveness of brain tumours. International Journal of Molecular Sciences. January 2023.

108. Losso J. The potential of dietary bioactive compounds against SARS-CoV-2 and COVID-19-induced endothelial dysfunction. Molecules (Basel, Switzerland). March 2022.

About the Author

Long interested in practical neuroscience, John D. MacArthur researched and wrote “The Human Brain” for the Franklin Institute Science Museum. His previous contributions to the Townsend Letter include seven reports: “Cell Phones and the Brain” (July 2002); “Too Much Copper, Too Little Zinc, and Cognitive Deterioration in Alzheimer’s Disease” (with George J. Brewer, MD) and “Overdosed: Fluoride, Copper, and Alzheimer’s Disease” (October 2013); “Fluoride and Preterm Birth” (November 2013); “Placental Fluorosis: Fluoride and Preeclampsia” (May 2015); “Prenatal Fluoride and Autism” (April 2016); “Fluoride and Mental Decay: Causation & Correlation” (October 2019). Links to these and John’s historical work are at johndmacarthur.com.