© 2020 PFPC - May 17, 2020
Last Entry Update: December 19, 2022
This forum investigates the pathophysiology of COVID-19 and compares findings to fluoride poisoning, pathways involving Gq/11 proteins, and the moderating/regulating effects of thyroid hormones.
We look at key events in cells, tissues, and the body's immune system, and list the literature documenting the similarities. It is an ongoing project - a collection of notes, for the time being.
While originally described as a disease causing acute-respiratory-distress-syndrome (ARDS), it is now believed that COVID-19 may involve multi-organ damage (Wang et al., 2020; Haeck et al., 2020; Atri et al., 2020; Qin et al., 2020). However, it is claimed that the pathways involving these varied conditions are not yet understood. There are over 2100 ongoing clinical trials underway, but to date none of these drugs have consistently proven effective (Liu et al., 2020). [UPDATE Sept. 2021: there are now over 8000 trials - Ed.]
In this forum, we hope to be able to show that pathways activated by aberrant Gq/11 signaling are at the core of both COVID-19 and fluoride poisoning and further, that these same pathways are regulated by thyroid hormones and TSH, the thyroid-stimulating hormone. Gq/11 are one of the four G protein families.
We have been able to trace almost all aspects of COVID-19 pathophysiology to pathways that are downstream of Gq/11 activation. As numerous agents already exist that target Gq/11 we hope that the information in this forum will contribute to finding effective therapeutic agents not just for COVID-19, but also for fluoride poisoning.
COVID-19 and Fluorosis
When we first researched COVID-19 and the pathways involved, we immediately noticed similarities to fluoride poisoning, or fluorosis.
For example, the pathways leading to lung conditions/damage observed in COVID-19 patients (Xiong et al., 2020) appear identical to those observed in workers exposed to fluorides (Wen et al., 2019).
Consider the following two statements:
(Xiong et al., 2020)"SARS-CoV-2 induced activation of apoptosis and P53 signalling pathway in lymphocytes may be the cause of patients' lymphopenia".
(Wen et al., 2019)"Long-term exposure to low level of fluoride induces apoptosis via p53 pathway in lymphocytes of aluminum smelter workers".
This was clear first evidence that some aspects of COVID-19 and fluoride poisoning involved overlapping or similar pathways. Further evidence was found rather easily, once we started looking for it.
Both, COVID-19 and fluoride poisoning, exhibit elevated levels of inflammatory biomarkers and cytokines, including IL-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and interleukin (IL)-2R (Atri et al., 2020; Qin et al., 2020; Varol et al., 2012; Lu et al., 2017; Sana et al., 2017; Afolabi et al., 2013).
Further, both increase NF-kappa B and cardiac troponins (Balsal, 2020; Oyagbemi et al., 2020; Wang et al., 2018; Sana et al., 2017).
IL-10 and TGF-b levels are also altered in both COVID-19 and fluoride poisoning (Wan et al., 2020; Xiong et al., 2020; Luo et al., 2017; Zhang et al., 2019).
There are other similarities.
As has been shown in animal studies of fluoride poisoning, liver damage is observed in some COVID-19 patients. Levels of ALT, AST, GGT are elevated in both conditions while albumin levels are reduced (Wang et al., 2020; Sun et al., 2020; Gu et al., 2020; Lu et al., 2017; Zhao et al., 2014; Kessabi et al., 1983; Xiong et al., 2007).
Blacks, who have a more sensitive thyroid status than whites, are at increased risk in both conditions (Millett et al., 2020; Akinkugbe et al., 2014).
Like in COVID-19, fluoride is more dangerous in patients suffering from glucose-6-phosphate dehydrogenase (G6PD) deficiency (Pornprasert et al., 2017; Kassi et al., 2020).
Numerous therapeutic agents proposed for treatment in COVID-19 have also been used to alleviate fluoride toxicity, such as resveratrol (Magrone at., 2020; Suzuki et al, 2018), melatonin (Martín Giménez et al., 2020; Zhao et al., 2017; Sana et al., 2017; Kumar et al., 2019), N-acetylcysteine (Assimakopoulos, 2020; Pawłowska-Góral et al., 2013), quercetin (Derosa et al., 2021; Nabavi et al., 2011), and Vitamin D (Martín Giménez et al., 2020; Kumar et al., 2012). Vitamin D deficiency is thought to be a risk factor in both conditions (Mitchell, 2020; Bondu et al., 2019).
We further focused our research on the G proteins Gq/11, as we have learned over the past 20 years that the majority of fluoride toxicity occurs via pathways regulated by the Gq/11 subfamily of G proteins. In biochemistry, fluoride is known as the "universal G protein activator", meaning it can act on all four G protein families. In the human body, the TSH receptor is the only known G-protein-coupled-receptor known to activate all four G protein families. Fluoride has been used as a TSH analogue in hundreds of studies.
- See: What are G proteins? viewtopic.php?f=86&t=2717
Each forum entry will list the correlations of COVID-19, fluoride poisoning, Gq/11 involvement, and thyroid hormones.
We will post as much of our research as we can - time permitting, in the hopes that it might be of benefit to all. Some of our friends in the scientific community are currently looking for therapeutic agents to combat COVID-19.
Perhaps this information might also alert others to the toxicity of fluoride, and help shed more light on the many adverse health effects caused by fluoride.
So far, not one study has yet investigated COVID-19 effects on the thyroid or tested for thyroid hormones and TSH levels in COVID-19 patients. [UPDATE Aug 20, 2020: The first study was e-published in July 2020, and more and more research is now being conducted. For the latest news, please see viewtopic.php?f=66&t=2040]
Topics in this forum:
Lung Damage: Apoptosis & p53 activation. viewtopic.php?f=66&t=1881
Cardiac Injury: Cardiac Troponins. viewtopic.php?f=66&t=1883
Renin-Angiotensin System (Ras)
Ras and ACE2
Angiotensin-II Type 1 Receptor - AT1R. viewtopic.php?f=66&t=4542
INF (Interferon). viewtopic.php?f=66&t=3665
NF-kappa B. viewtopic.php?f=66&t=1888
C-Reactive Protein (CRP). viewtopic.php?f=66&t=1886
Tumor Necrosis Factor (TNF-α). viewtopic.php?f=66&t=1895
Creatine Kinase. viewtopic.php?f=66&t=1999
Virus Replication and Ca2+
Alzheimer's Disease. viewtopic.php?f=66&t=4210
- Resveratrol. viewtopic.php?f=66&t=1900
- Melatonin. viewtopic.php?f=66&t=1920
- Vitamin D. viewtopic.php?f=66&t=1944
- Cathepsin L
- N-acetylcysteine. viewtopic.php?f=66&t=2006
- Dexamethasone. viewtopic.php?f=66&t=2196
- Quercetin. viewtopic.php?f=66&t=3007&p=3525#p3525
- Selenium. viewtopic.php?f=66&t=3116
- Fluvoxamine/fluoxetine. viewtopic.php?f=66&t=3810&p=4508#p4508
Age and the Immune System.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency. viewtopic.php?f=66&t=1887
Liver Function. viewtopic.php?f=66&t=1945
Blood Pressure. viewtopic.php?f=68&t=1973
Menstrual Changes. viewtopic.php?f=66&t=3642
The 3rd Loop
- Diabetes. viewtopic.php?f=66&t=2048
- Heart Disease. viewtopic.php?f=66&t=2052
- Atherosclerosis. viewtopic.php?f=66&t=2050
- Kidney Injury. viewtopic.php?f=66&t=2058
- Metabolic Syndrome. viewtopic.php?f=66&t=3592
Numerous questions/discussion points:
1) Two conditions - COVID-19 and fluoride poisoning - apparently involve similar damage in various organs, as can be witnessed in many studies from around the world. In contrast to COVID-19, fluoride poisoning has been largely neglected and adverse health effects of fluoride are often downplayed by many Western public health agencies. Fluorosis is endemic in at least 25 countries across the globe, China and India being the worst affected (Pramanik, 2017). In India alone, 62 million people are affected, 6 million of whom are children under 14 years old (Srikanth, 2009). Even in Western countries, fluoride poisoning is ever-increasing. The majority of US teens now have dental fluorosis - a sign that fluoride intake was excessive during crucial times of development (Wiener et al., 2018).
2) The two conditions share identical pathways. If treatments work in the fight against COVID-19, is it possible that they might also be of benefit in fluoride poisoning? And vice versa? Could the vast amount of research on fluoride effects be of benefit in assessing COVID-19? Would/could treatment involve specific inhibitors of the Gq/11 family? Correction of thyroid status?
3) Are those living in endemic fluorosis or iodine-deficient areas at higher risk of COVID-19 infection? Increased organ damage? Does altitude play a role?
4) As the involvement of thyroid hormones can be documented - does thyroid status influence disease severity in COVID-19, as it does in fluoride poisoning? Serum ACE activities change in proportion to thyroid hormone levels. What effects does COVID-19 have on the thyroid and thyroid hormone metabolism?
PFPC Canada - May 17, 2020
Comments may be sent to info2 AT poisonfluoride.com
Afolabi OK, Oyewo EB, Adekunle AS, Adedosu OT, Adedeji AL - "Oxidative indices correlate with dyslipidemia and pro-inflammatory cytokine levels in fluoride-exposed rats" Arh Hig Rada Toksikol 64(4):521-9 (2013) doi: 10.2478/10004-1254-64-2013-2351. PMID: 24384758.
PFPC Library Link
Akinkugbe A, Iafolla T, Chattopadhyay A, Garcia I, Adams A, Kingman A - "The role of partial recording protocols in reporting prevalence and severity of dental fluorosis" Community Dent Oral Epidemiol 42(6):563-71 (2014) doi: 10.1111/cdoe.12115. Epub 2014 Jul 4. PMID: 24995860; PMCID: PMC4245329
Assimakopoulos SF, Marangos M - "N-acetyl-cysteine may prevent COVID-19-associated cytokine storm and acute respiratory distress syndrome" Med Hypotheses 140:109778 (2020) doi: 10.1016/j.mehy.2020.109778. Epub ahead of print. PMID: 32344315; PMCID: PMC7195028
Atri D, Siddiqi HK, Lang J, Nauffal V, Morrow DA, Bohula EA - "COVID-19 for the Cardiologist: A Current Review of the Virology, Clinical Epidemiology, Cardiac and Other Clinical Manifestations and Potential Therapeutic Strategies" JACC Basic Transl Sci Apr 10 (2020) doi: 10.1016/j.jacbts.2020.04.002. Epub ahead of print. PMID: 32292848; PMCID: PMC7151394.
https://www.ncbi.nlm.nih.gov/pmc/articl ... f/main.pdf
Bansal M - "Cardiovascular disease and COVID-19" Diabetes Metab Syndr 14(3):247-250 (2020) doi: 10.1016/j.dsx.2020.03.013. Epub 2020 Mar 25. PMID: 32247212; PMCID: PMC7102662.
Bondu JD, Seshadri MS, Selvakumar R, Fleming JJ - "Effects of Fluoride on Bone in an Animal Model of Vitamin D Deficiency" Indian J Clin Biochem 34(1):60-67. doi: 10.1007/s12291-017-0709-7 (2019) Epub 2017 Nov 13. PMID: 30728674; PMCID: PMC6346609
CDC, Prevalence and Severity of Dental Fluorosis in the United States, 1999-2004, NCHS Data Brief No. 53, November 2010
Derosa G, Maffioli P, D'Angelo A, Di Pierro F - "A role for quercetin in coronavirus disease 2019 (COVID-19)" Phytother Res 35(3):1230-1236 (2021)
Gu X, Li X, An X, Yang S, Wu S, Yang X, Wang H - "Elevated serum aspartate aminotransferase level identifies patients with coronavirus disease 2019 and predicts the length of hospital stay" J Clin Lab Anal - Jun 2:e23391 (2020) doi: 10.1002/jcla.23391. Epub ahead of print. PMID: 32488888
Haeck G, Ancion A, Marechal P, Oury C, Lancellotti P - "COVID-19 et maladies cardiovasculaires [COVID-19 and cardiovascular diseases]" Rev Med Liege 75(4):226-232 (2020) French. PMID: 32267110
https://www.rmlg.ulg.ac.be/aboel.php?nu ... &langue=EN
Hui EK, Nayak DP - "Role of G protein and protein kinase signalling in influenza virus budding in MDCK cells" J Gen Viro 83(Pt 12):3055-3066 (2002) doi: 10.1099/0022-1317-83-12-3055. PMID: 12466482
Jialili A, Abasi K, Maimaitizunong, Zhang L, Li XJ - "Influence of propofol on Gq/11 protein in kidney during acute respiratory distress syndrome" Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 18(12):724-6 (2006) Chinese. PMID: 17166350
Kassi EN, Papavassiliou KA, Papavassiliou AG - "G6PD and chloroquine: Selecting the treatment against SARS-CoV-2?" J Cell Mol Med 24(9):4913-4914 (2020) doi: 10.1111/jcmm.15312. Epub 2020 Apr 16. PMID: 32281268; PMCID: PMC7205832
Kessabi M, Khouzaimi M, Braun JP, Hamliri A - "Serum biochemical effects of fluoride on cattle in the Darmous area" Vet Hum Toxicol 25(6):403-6 (1983) PMID: 6659304
Kumar J, Haldar C, Verma R - "Fluoride Compromises Testicular Redox Sensor, Gap Junction Protein, and Metabolic Status: Amelioration by Melatonin" Biol Trace Elem Res (2019) doi: 10.1007/s12011-019-01946-6. Epub ahead of print. PMID: 31828722
https://link.springer.com/article/10.10 ... 19-01946-6
Kumar N, Sood S, Arora B, Singh M, Beena, Roy PS - "To Study the Effect of Vitamin D and E on Sodium-Fluoride-induced Toxicity in Reproductive Functions of Male Rabbits." Toxicol Int 19(2):182-7 (2012) doi: 10.4103/0971-6580.97220. PMID: 22778518; PMCID: PMC3388764
Liu T, Luo S, Libby P, Shi GP - "Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients" Pharmacol Ther May 26:107587 (2020) doi: 10.1016/j.pharmthera.2020.107587. Epub ahead of print. PMID: 32470470; PMCID: PMC7255230
Lu Y, Luo Q, Cui H, Deng H, Kuang P, Liu H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L - "Sodium fluoride causes oxidative stress and apoptosis in the mouse liver" Aging (Albany NY) 9(6):1623-1639 (2017) doi: 10.18632/aging.101257. PMID: 28657544; PMCID: PMC5509460.
Luo Q, Cui H, Deng H, Kuang P, Liu H, Lu Y, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L - " Sodium fluoride induces renal inflammatory responses by activating NF-κB signaling pathway and reducing anti-inflammatory cytokine expression in mice" Oncotarget 8(46):80192-80207 (2017) doi: 10.18632/oncotarget.19006. PMID: 29113295; PMCID: PMC5655190.
Magrone T, Magrone M, Jirillo E - "Focus on Receptors for Coronaviruses with Special Reference to Angiotensin-converting Enzyme 2 as a Potential Drug Target - A Perspective" Endocr Metab Immune Disord Drug Targets (2020) doi: 10.2174/1871530320666200427112902. Epub ahead of print. PMID: 32338224.
Martín Giménez VM, Inserra F, Tajer CD, Mariani J, Ferder L, Reiter RJ, Manucha W - "Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment" Life Sci 254:117808. (2020) doi: 10.1016/j.lfs.2020.117808. Epub ahead of print. PMID: 32422305; PMCID: PMC7227533
Millett GA, Jones AT, Benkeser D, Baral S, Mercer L, Beyrer C, Honermann B, Lankiewicz E, Mena L, Crowley JS, Sherwood J, Sullivan P - "Assessing Differential Impacts of COVID-19 on Black Communities" Ann Epidemiol (2020) doi: 10.1016/j.annepidem.2020.05.003. Epub ahead of print. PMID: 32419766; PMCID: PMC7224670
Mitchell F - "Vitamin-D and COVID-19: do deficient risk a poorer outcome?" Lancet Diabetes Endocrinol S2213-8587(20)30183-2 (2020) doi: 10.1016/S2213-8587(20)30183-2. Epub ahead of print. PMID: 32445630
Nabavi SF, Moghaddam AH, Nabavi SM, Eslami S - "Protective effect of curcumin and quercetin on thyroid function in sodium fluoride intoxicated rats" Fluoride 44: 147-152 (2011)
https://www.fluorideresearch.org/443/fi ... 52_sfs.pdf
Pawłowska-Góral K, Kurzeja E, Stec M - "N-acetylcysteine protects against fluoride-induced oxidative damage in primary rat hepatocytes" Toxicol In Vitro 27(8):2279-82 (2013) doi: 10.1016/j.tiv.2013.09.019. Epub 2013 Oct 2. PMID: 24095861
Pornprasert S, Wanachantararak P, Kantawong F, Chamnanprai S, Kongpan C, Pienthai N, Yanola J, Duangmano S, Prasannarong M - "Excessive fluoride consumption increases haematological alteration in subjects with iron deficiency, thalassaemia, and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency" Environ Geochem Health 39(4):751-758 (2017)
doi: 10.1007/s10653-016-9845-x. Epub 2016 Jun 18. PMID: 27318827
Pramanik S, Saha D - "The genetic influence in fluorosis" Environ Toxicol Pharmacol 56:157-162 (2017) doi: 10.1016/j.etap.2017.09.008. Epub 2017 Sep 15. PMID: 28938149.
Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, Xie C, Ma K, Shang K, Wang W, Tian DS - "Dysregulation of immune response in patients with COVID-19 in Wuhan, China" Clin Infect Dis Mar 12:ciaa248 (2020) doi: 10.1093/cid/ciaa248. Epub ahead of print. PMID: 32161940; PMCID: PMC7108125
https://www.ncbi.nlm.nih.gov/pmc/articl ... iaa248.pdf
Sana S, Ghosh S, Das N, Sarkar S, Mandal AK - "Vesicular melatonin efficiently downregulates sodium fluoride-induced rat hepato- and broncho-TNF-α, TGF-β expressions, and associated oxidative injury: a comparative study of liposomal and nanoencapsulated forms" Int J Nanomedicine 12:4059-4071(2017) doi: 10.2147/IJN.S12411
Srikanth R - "Challenges of sustainable water quality management in rural India" Curr Sci 97:317-25 (2009)
Sun Y, Dong Y, Wang L, Xie H, Li B, Chang C, Wang FS - "Characteristics and prognostic factors of disease severity in patients with COVID-19: The Beijing experience" J Autoimmun 102473 (2020) doi: 10.1016/j.jaut.2020.102473. Epub ahead of print. PMID: 32439209; PMCID: PMC7180376
https://www.sciencedirect.com/science/a ... via%3Dihub
Suzuki M, Ikeda A, Bartlett JD - " Sirt1 overexpression suppresses fluoride-induced p53 acetylation to alleviate fluoride toxicity in ameloblasts responsible for enamel formation" Arch Toxicol 92(3):1283-1293 (2018) doi: 10.1007/s00204-017-2135-2. Epub 2017 Nov 28. PMID: 29185024; PMCID: PMC6667832.
Varol E, Aksoy F, Icli A, Arslan A, Yuksel O, Ersoy IH, Varol S, Dogan A - "Increased plasma neopterin and hs-CRP levels in patients with endemic fluorosis" Bull Environ Contam Toxicol 89(5):931-6 (2012) doi: 10.1007/s00128-012-0801-x. Epub 2012 Aug 25. PMID: 22926451.
Wan S, Yi Q, Fan S, Lv J, Zhang X, Guo L, Lang C, Xiao Q, Xiao K, Yi Z, Qiang M, Xiang J, Zhang B, Chen Y, Gao C - "Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients" Br J Haematol 189(3):428-437 (2020) doi: 10.1111/bjh.16659. Epub 2020 Apr 20. PMID: 32297671.
Wang T, Du Z, Zhu F, Cao Z, An Y, Gao Y, Jiang B - "Comorbidities and multi-organ injuries in the treatment of COVID-19" Lancet 21;395(10228):e52 (2020) doi: 10.1016/S0140-6736(20)30558-4. Epub 2020 Mar 11. PMID: 32171074.
https://www.thelancet.com/pdfs/journals ... 0558-4.pdf
Wang HW, Liu J, Zhao J, Lin L, Zhao WP, Tan PP, Tian WS, Zhou BH - "Ca2+ metabolic disorder and abnormal expression of cardiac troponin involved in fluoride-induced cardiomyocyte damage" Chemosphere 201:564-570 (2018) doi: 10.1016/j.chemosphere.2018.03.053. Epub 2018 Mar 7. PMID: 29533806.
Wang Y, Liu S, Liu H, Li W, Lin F, Jiang L, Li X, Xu P, Zhang L, Zhao L, Cao Y, Kang J, Yang J, Li L, Liu X, Li Y, Nie R, Mu J, Lu F, Zhao S, Lu J, Zhao J - "SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19" J Hepatol 10:S0168-8278(20)30294-4 (2020) doi: 10.1016/j.jhep.2020.05.002. Epub ahead of print. PMID: 32437830; PMCID: PMC7211738
Wen P, Wei X, Liang G, Wang Y, Yang Y, Qin L, Pang W, Qin G, Li H, Jiang Y, Wu Q - "Long-term exposure to low level of fluoride induces apoptosis via p53 pathway in lymphocytes of aluminum smelter workers." Environ Sci Pollut Res Int 26(3):2671-2680 (2019). doi: 10.1007/s11356-018-3726-z. Epub 2018 Nov 26. PMID: 30478774
Wiener RC, Shen C, Findley P, Tan X, Sambamoorthi U - "Dental fluorosis over time: a comparison of National Health and Nutrition Examination Survey data from 2001–2002 and 2011–2012" J Dent Hyg 92(1):23–9 (2018)
Xiong X, Liu J, He W, Xia T, He P, Chen X, Yang K, Wang A - "Dose-effect relationship between drinking water fluoride levels and damage to liver and kidney functions in children" Environ Res 103(1):112-6 (2007) doi: 10.1016/j.envres.2006.05.008. Epub 2006 Jul 10. PMID: 16834990.
Xiong Y, Liu Y, Cao L, Wang D, Guo M, Jiang A, Guo D, Hu W, Yang J, Tang Z, Wu H, Lin Y, Zhang M, Zhang Q, Shi M, Liu Y, Zhou Y, Lan K, Chen Y - "Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients" Emerg Microbes Infect 9(1):761-770 (2020). doi: 10.1080/22221751.2020.1747363. PMID: 32228226; PMCID: PMC7170362
Zhang J, Jiang N, Yu H, Yu X, Guo F, Zhao Z, Xu H - "Requirement of TGFβ Signaling for Effect of Fluoride on Osteoblastic Differentiation" Biol Trace Elem Res 187(2):492-498 (2019) doi: 10.1007/s12011-018-1387-x. Epub 2018 May 16. PMID: 29770951
Zhang L, Leifate B, Kelala A - "The dynamic alteration in Gq/11 protein expression in multiple organs during acute respiratory distress syndrome in rat". Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 22(8):477-81 (2010) Chinese. PMID: 20804650
Zhao J, Fu B, Peng W, Mao T, Wu H, Zhang Y - "Melatonin protect the development of preimplantation mouse embryos from sodium fluoride-induced oxidative injury" Environ Toxicol Pharmacol 54:133-141 (2017) doi: 10.1016/j.etap.2017.06.014. Epub 2017 Jun 29. PMID: 28728132.
Zhao L, Yu Y, Deng C - "Expression of sonic hedgehog signaling pathway and its inhibition by cyclopamine in rat liver with chronic fluorosis" Zhonghua Bing Li Xue Za Zhi 43(12):814-9 (2014) Chinese. PMID: 25623978