Did we get Covid-19 disease mechanisms all wrong? Part 3

The third phase of Covid-19’s mechanism of disease has a lot to answer for – but it’s not all bad news

This is the final part of a three-part series. Read Part 1 here, and Part 2 here.

In this latest instalment, author Janine Gallizia explains how SARS-CoV-2 has directly contributed to the rise in incidences of cancer, heart and vascular diseases including impaired myocardial contractility, ‘sudden death syndrome’, abnormal blood clotting, cognitive decline and Alzheimer’s Disease, nerve damage, Creutzfeldt-Jakob disease (CJD), mitochondrial dysfunction, infertility… and now, also autism. It’s not all bad news, however. Read on to find out how understanding this mechanism also illuminates opportunities for a new stream of natural, safe and effective therapeutics.

The collapse of cell signalling

By Janine Gallizia

Survival mechanisms are part of every organism’s existence. Plants, including trees, shed their leaves, flowers, fruits and branches in response to environmental stressors such as harsh weather, pathogens, deficiencies or structural damage. This strategy for preserving energy and resources for survival is called abscission.

The human body uses a similar process. By reducing ‘less essential’ functions (for example hair, nail and skin growth and repair) when the body is under stress, the body can prioritise resources, and channel them towards vital functions such as regulating heart rate, controlled breathing, regulating immune responses, energy production and temperature regulation. If required, it can also elicit programmed cell death to eliminate damaged cells and recycle essential nutrients, as part of the cell’s stress response to preserve health. This ensures the cell prioritizes functions to meet challenges in its environment.

In the human body this process is known as ‘resource prioritisation’ and it’s part of the cellular stress response, regulating resource allocation to ensure vital functions are maintained, even if it means temporarily reducing or eliminating less essential ones, just as a tree drops leaves and branches to preserve health when under stress. However, should the stress continue over a long period of time, the prolonged reduction of resources towards less essential functions may lead to the accumulation of signs and symptoms of tissue dysfunction and damage, such as hair loss, slow healing wounds, fatigue, or more serious symptoms such as brain fog or a reduction in vision or hearing. 

For cells to be able to adapt to their surroundings, they must be aware of changes as they occur. Cells communicate with each other and can coordinate an adapted response to environmental stressors such as invading pathogens, nutrient deficiencies, emotional stress, and so on. They do this by using an intricate communication system called signal transduction, which triggers the secretion of signalling molecules such as hormones and cytokines, to inform cells of changes in the cell’s surroundings.

Signal transduction is the process by which a cell detects information signals in the microenvironment surrounding the cell, and relays this information into the cell to trigger modifications in cell behaviour to suit the changes occurring. Cell signalling pathways are used to communicate information between cells to mount an adapted coordinated response. Signal transduction and signalling pathways work together: signal transduction detects changes in the cell’s environment, whilst signalling pathways act as cell communication networks that inform cells of the necessary actions required to ensure appropriate cellular behaviour occurs. This cell awareness and adaptation is crucial for cellular function and survival, allowing tissues and organs to function normally, even in stressful situations. Cell signalling pathways regulate genes and gene expression, cell proliferation and growth, elicited cell death including autophagy, cell adhesion and cell metabolism.

Under stress, the body will prioritize resources and energy essential for its survival. However, if deficiencies develop, the lack of certain resources can severely jeopardize cell function, including the disruption of cell signalling pathways. This can lead to seemingly unrelated signs and symptoms in the body. This scenario is taking place in patients suffering from Covid-19, Long-Covid and post Covid-19 injection symptoms, many of which are reversible once the true cause behind the dysfunction is corrected.

The SARS-CoV-2, copper enzymes and signalling pathways

As we learned in Part 1, SARS-CoV-2 depletes essential CD4+ T immune cell numbers, leading to a weakened immune response. A paper published on the U.S.’ National Institute of Health website directs our attention to the role of the thymus for CD4 cell maturation, stating “CD4 T lymphocytes are a part of the human T-lymphocyte cells that are produced in the bone marrow and eventually mature in the thymus.”¹

Immunity is essential for survival. A drastic reduction of immune cells triggers an emergency stress response, whereby the body must produce immune cells at a faster pace than normal. The thymus is a small organ located in the upper chest, between the lungs and below the thyroid but above the heart. It requires copper to maintain its structure and function, and to replenish and maintain immune cell levels, including CD4 cell numbers.

Under an emergency stress response such as exposure to SARS-CoV-2, resource prioritisation directs copper reserves to the thymus for increased CD4 production, reducing copper availability for other copper-dependent functions. The longer the period of CD4 cell reduction, the greater the copper deficiency becomes for other copper-dependent requirements.

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A copper deficiency is a very serious problem that can be fatal, as it triggers a cascade of disruption in tissue maintenance and repair, DNA structure and expression, mitochondrial dysfunction and a reduction of energy production, activity of cuproenzymes which are enzymes that contain copper as a cofactor (see figure 1), blood clotting, myelin synthesis, the synthesis of neurotransmitters such as dopamine, norepinephrine, and serotonin, neurotransmitter signalling, cell signalling (see figure 2) and all the downstream effects of the above. A copper deficiency largely goes undetected, yet leads to vast and varied seemingly unconnected symptoms throughout the body.

Figure 1. A selection of copper-dependent cuproenzymes

Figure 2. A selection of copper dependant cell signaling pathways or receptors.

If SARS-CoV-2 reduces CD4 numbers inducing a copper deficiency, and copper is required by the thymus for its development and function, damage and dysfunction of the thymus should be a symptom of Covid-19. It is, as evidenced in a paper by Rosichini M and others published in The Journal of Allergy and Clinical Immunology. The authors state, “We showed that patients with COVID-19 had reduced thymic function that was inversely associated with the severity of the disease.” They conclude, “Our data demonstrate that the human thymus is a target of SARS-CoV-2 and thymic function is altered following infection.”²

As SARS-CoV-2 and HIV share GP120 on their spike protein binding site, both viruses induce CD4+ T cell loss.³ We should therefore also see the same dysfunction of the thymus in HIV patients, and HIV researchers have identified the importance of this finding for impaired immune recovery after HIV infection. In a paper by Dos Santos Guedes MC and others published in Viruses, the authors further our understanding of the slow immune recovery in Covid-19 patients, reflecting on the CD4 induced reduction experienced with HIV infection. They state:

“Two main processes have been associated with the imbalance in T cell homeostasis and, consequently, with the impaired immunological recovery: the decrease in thymic production of T lymphocytes and the excessive destruction of these cells.”⁴

Low immune cell count impairs immune recovery in Long-Covid and the Covid-19 injected population. This explains the activation of dormant viruses in the body, such as Epstein Barr (EBV), Herpes zoster (shingles) or Covid-19 re-infection. Several papers confirm this, including a paper published in the European Journal of Cell Biology,⁵ where the authors explain, “Protective immunity against EBV is mediated by T cells.” In a paper published in Pathogens and Immunity, the authors Jin W and others state “CD4+ T cells are a critical component of effective immune responses to varicella zoster virus (VZV).”⁶ Elsewhere, Zeng L and others connected the activation of dormant viral infections in HIV patients with the reduction in CD4 numbers. Their paper in Clinical, Cosmetic and Investigational Dermatology confirms, “It was pointed out that the incidence of disseminated herpes zoster increased with the decrease of CD4 T cells.”⁷

The pieces of the Covid-19 puzzle come together with a brillant paper by Raha S and others published in Medical Hypotheses titled, “Is copper beneficial for COVID-19 patients?” where the authors speak of copper’s (Cu) role in immune function:

“Cu is involved in the functions of critical immune cells such as T helper cells, B cells, neutrophils natural killer (NK) cells, and macrophages. These blood cells are involved in the killing of infectious microbes, in cell-mediated immunity and the production of specific antibodies against the pathogens. Cu-deficient humans show an exceptional susceptibility to infections due to the decreased number and function of these blood cells.”⁸

The authors expand on copper’s role in fighting microbes and viruses, stating: 

“Besides, Cu can kill several infectious viruses such as bronchitis virus, poliovirus, human immunodeficiency virus type 1(HIV-1), other enveloped or nonenveloped, single- or double-stranded DNA and RNA viruses. Moreover, Cu has the potent capacity of contact killing of several viruses, including SARS‐CoV‐2.”⁹

Well before Covid-19 injections were available, the American Environmental Protection Agency (EPA) also confirmed copper’s ability to kill SARS-CoV-2 on contact. On February 10th, 2021 the EPA published an official press release regarding copper’s effect on SARS-CoV-2. The press release reads:

“Today, the U.S. Environmental Protection Agency (EPA) is announcing that certain copper alloys provide long-term effectiveness against viruses, including SARS-CoV-2, the virus that causes COVID-19. As a result of EPA’s approval, products containing these copper alloys can now be sold and distributed with claims that they kill viruses that come into contact with them.”¹⁰

The document continues, specifying:

 “EPA expects these products to eliminate 99.9 percent of SARS-CoV-2, the virus that causes COVID-19, within two hours.”¹¹ (my bold)

Please note the mention of “certain copper alloys”. Not all copper is equal; many forms of copper are toxic.

Copper’s ability to kill SARS-CoV-2 on contact was confirmed by other scientists in a paper published in Biometals, titled simply “Antiviral properties of copper and its alloys to inactivate covid-19 virus.”¹²

Covid-19 injections used either new mRNA technology or an adenovirus vector to command human cells to produce the SARS-CoV-2 spike protein for an unknown period of time, as confirmed in a paper by Theoharides TC and Conti Pin, titled “Be aware of SARS-CoV-2 spike protein: There is more than meets the eye.” Published in the Journal of Biological Regulators and Homeostatic Agents, the authors explain:

“The COVID-19 pandemic necessitated the rapid production of vaccines aimed at the production of neutralizing antibodies against the COVID-19 spike protein required for the corona virus binding to target cells. The best well-known vaccines have utilized either mRNA or an adenovirus vector to direct human cells to produce the spike protein against which the body produces mostly neutralizing antibodies.”¹³

The continuous production of SARS-CoV-2 spike protein continuously reduces CD4 cell numbers, continuously requiring increased levels of copper by the thymus to maintain its structure and replenish CD4 cell levels. As copper resource prioritization occurs, copper levels are reduced for ‘less essential’ functions. Due to the ongoing SARS-CoV-2 spike protein production occurring in human cells in the Covid-19 injected population, copper becomes unavailable in sufficient quantity for other copper-dependent functions, eventually triggering a cascade of vast and varied, seemingly unconnected symptoms throughout the body. (See Figure 3. Covid-19 symptoms vs. Copper deficiency symptoms below). 

Increased copper through diet or a specific form of non-toxic copper supplement, not only corrects copper deficiency symptoms, it also increases immune cell production, including CD4+ T cell count.

The journal Nutrition published a key paper in 1993, titled “Copper repletion restores the number and function of CD4 cells in copper-deficient rats”. The authors explain the importance of copper to replete immune cell levels, stating, “Copper is essential for the optimal function of the cellular and humoral branches of the immune system”, as copper “is required for maturation and signal-mediated proliferation of lymphocytes.” They also state that the “activities of Cu-deficient neutrophils were restored to normal when rats were fed diet containing adequate Cu for 1 wk.” [1 week]¹⁴

It is well recognized that most post Covid-19 infection and injection symptoms cannot be explained by a viral infection, specifically as many develop and escalate well after SARS-CoV-2 infection has cleared. The majority of post Covid-19 infection or Covid-19 injection symptoms stem from a combination of dysfunctional RAS (renin-angiotensin-system) due to SARS-CoV-2 damage to the kidney’s distal tubules, and symptoms of a severe copper deficiency, which creates a zinc-copper imbalance. Restoring RAS and copper levels are both achievable processes.

The Copper Paradox

Most doctors are unaware of the massive copper paradox debate currently taking place in the scientific field. Science has identified the importance of copper deficiency and copper toxicity in the development of many chronic disease such as cancer¹⁵¹⁶¹⁷, heart and vascular diseases including impaired myocardial contractility and ‘sudden death syndrome’¹⁸¹⁹²⁰²¹²²²³, blood clotting disorders²⁴²⁵, cognitive decline and Alzheimers Disease²⁶²⁷²⁸²⁹³⁰, nerve damage³¹³²³³, prion disease (Creutzfeldt-Jakob disease (CJD), mad cow disease, kuru)³⁴³⁵³⁶³⁷, mitochondrial dysfunction³⁸³⁹⁴⁰ infertility⁴¹⁴²⁴³ and even autism⁴⁴⁴⁵⁴⁶.

Science is currently faced with a copper paradox, recognising the complexity of observed copper deficiency, copper toxicity and a zinc-copper ratio imbalance all at the same time in many chronic diseases. As such, the solution is not simply copper supplementation, particularly if the situation is ongoing, as copper supplements often lead to copper accumulation, tissue toxicity and a zinc-copper ratio imbalance. Disruption in correct zinc-copper levels is observed in Long-Covid-19 and post Covid-19 injection patients⁴⁷⁴⁸ ⁴⁹, leading to a cascade of vast and varied symptoms due to copper’s role in cell health and survival. Thorough understanding of copper from effective copper sources is required before supplementing with copper to effectively reduce symptoms and improve health.

During the early days of Covid-19, when the origin of illness was still unknown, zinc supplementation was suggested to boost immunity. As a short-term solution zinc is an effective molecule also required by the thymus to maintain immune function. However, long-term zinc supplement induces a zinc-copper imbalance, creating what could be perceived as Covid-19 or Long-Covid due to long-term zinc supplementation.

In a paper published in The American Journal of Medicine, titled “The COVID-19 Pandemic and Zinc-Induced Copper Deficiency: An Important Link”, the authors Francis Z. and others state:

"Zinc supplementation has made headlines as a way to bolster the immune system during the coronavirus (COVID-19) pandemic, spurred by reports of possible reduction in symptoms of acute respiratory infections. Unfortunately, zinc toxicity is not a benign syndrome and has been shown to interfere with the body's absorption of available copper, even at relatively low doses above the Recommended Dietary Allowance.”⁵⁰

A paper by George J. Brewer, Emeritus professor in the departments of Human Genetics and Internal Medicine at the University of Michigan, reminds us of the suspected origin of copper toxicity plaguing humanity and some of the sources of this toxic copper accumulation. Titled “Copper toxicity in Alzheimer's disease: Cognitive loss from ingestion of inorganic copper” and published in Journal of Trace Elements in Medicine and Biology, it states:

“In this review I present the hypothesis that a toxic substance, inorganic copper, ingested from drinking water and vitamin/mineral supplements containing inorganic copper, is at least partially causal of the epidemic of Alzheimer's disease (AD) we are seeing in developed countries.”⁵¹

Figure 3. Covid-19 symptoms vs copper-dependent cuproenzymes

Summary

There are three distinct phases behind Covid-19 illness post Covid-19 infection, Long-Covid and post Covid-19 injection.

Phase one: The SARS-CoV-2 spike protein binds to α4β7 integrin located on the surface of CD4+ T immune cells, allowing the virus to enter the immune cells. The α4β7 integrin then binds to MAdCAM-1 on the intestinal lining, allowing the infiltrated CD4+ T cells to carry SARS-CoV-2 into mucosal tissues, like a Trojan horse, where the virus is able to replicate and be disseminated throughout the body.

Phase two: SARS-CoV-2 induces severe damage to the kidney’s distal convoluted tubules, damaging the macular densa cells that are crucial for the regulation of the renin-angiotensin-system (RAS). This leads to a reduction in renin synthesis and release, consequentially reducing the level of ACE2 resulting in fluid imbalance, swelling/edemas, chronic inflammation, renal dysfunction, cardiovascular conditions, pulmonary complications, skin eruptions, lymphatic congestion and reduced drainage which impairs the body’s ability to clear SARS-CoV-2 viral matter, including the spike protein and other cellular waste, leading to alterations in the pH of the cell microenvironment, microbiota imbalance and tissue damage and dysfunction.

Phase three: The continuous production of SARS-CoV-2 spike protein in human cells reduces CD4 cell numbers, continuously requiring increased levels of copper by the thymus to maintain its structure and to replenish CD4 cell levels. As copper resource prioritization occurs, copper levels are reduced for ‘less essential’ functions. Due to the ongoing SARS-CoV-2 spike protein production in human cells of the Covid-19 injected population, copper becomes unavailable in sufficient quantity for other copper-dependent functions, eventually triggering a cascade of vast and varied, seemingly unconnected symptoms throughout the body. 

A severe copper deficiency is a very serious problem that can lead to the development of many chronic diseases and eventually be fatal.

A severe copper deficiency triggers a cascade of chaos in the body such as: reduced tissue maintenance and repair, abnormal DNA structure and expression, incorrect protein folding such as the formation of prions and amyloid plaques, mitochondrial dysfunction, reduced energy production, reduced activity of cuproenzymes (enzymes that require copper as a cofactor), abnormal blood clotting, reduced myelin synthesis, impaired synthesis of neurotransmitters such as dopamine, norepinephrine, and serotonin and neurotransmitter signalling pathways, disruption of the multiple essential cell signalling pathways, and all the downstream effects of the above.

Conclusion

SARS-CoV-2 has devastated world health and economies for four years. The loss of human life and incapacitation continues with the rise of vast and varied, seemingly unrelated symptoms and pathologies, the majority stemming from a severe copper deficiency or zinc-copper imbalance and damage to the kidney tubules.

A zinc-copper imbalance or deficiency can be corrected through dietary changes and careful supplementation with a specific non-toxic copper alloy. I will address successful copper therapeutics in another paper.

Although food sources of both zinc and copper are preferred, levels of copper in the food chain are far lower than they once were. The industrialisation of food, Big Farming and the use of herbicides and pesticides has increased crop production but reduced essential nutrients in the foods available. As a result, restoration from severe nutrient deficiencies through diet is complicated, and knowledge of how nutrient synergies work to increase nutrient delivery and absorption is essential.   

At a time when humanity is being directed towards the domination of AI systems to regulate almost all industries, including farming and healthcare, we are faced with a life-changing dilemma: has biology failed us in healthcare? Is monitoring and regulating human health with a new generation of AI devices the solution? This debate is too deep for this paper, but it is evident that knowledge of ancient health fundamentals used throughout history and largely omitted with dramatic consequences in western medicine, offers opportunities for a new breed of natural, safe and effective therapeutics.

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1. Battistini Garcia SA, Guzman N. Acquired Immune Deficiency Syndrome CD4+ Count. [Updated 2023 Aug 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513289/    

2. Rosichini M, Bordoni V, Silvestris DA, Mariotti D, Matusali G, Cardinale A, Zambruno G, Condorelli AG, Flamini S, Genah S, Catanoso M, Del Nonno F, Trezzi M, Galletti L, De Stefanis C, Cicolani N, Petrini S, Quintarelli C, Agrati C, Locatelli F, Velardi E. SARS-CoV-2 infection of thymus induces loss of function that correlates with disease severity. J Allergy Clin Immunol. 2023 Apr;151(4):911-921. doi: 10.1016/j.jaci.2023.01.022. Epub 2023 Feb 8. PMID: 36758836; PMCID: PMC9907790. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9907790/

3. Peng X, Ouyang J, Isnard S, Lin J, Fombuena B, Zhu B, Routy JP. Sharing CD4+ T Cell Loss: When COVID-19 and HIV Collide on Immune System. Front Immunol. 2020 Dec 15;11:596631. doi: 10.3389/fimmu.2020.596631. PMID: 33384690; PMCID: PMC7770166. https://pubmed.ncbi.nlm.nih.gov/33384690/

4. Dos Santos Guedes MC, Carvalho-Silva WHV, Andrade-Santos JL, Brelaz-de-Castro MCA, Souto FO, Guimarães RL. Thymic Exhaustion and Increased Immune Activation Are the Main Mechanisms Involved in Impaired Immunological Recovery of HIV-Positive Patients under ART. Viruses. 2023 Feb 5;15(2):440. doi: 10.3390/v15020440. PMID: 36851655; PMCID: PMC9961132. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9961132/

5. Josef Mautner, Georg W. Bornkamm, The role of virus-specific CD4+ T cells in the control of Epstein-Barr virus infection, European Journal of Cell Biology, Volume 91, Issue 1, 2012. https://www.sciencedirect.com/science/article/abs/pii/S0171933511000173

6. Jin W, Fang M, Sayin I, Smith C, Hunter JL, Richardson B, Golden JB, Haley C, Schmader KE, Betts MR, Tyring SK, Cameron CM, Cameron MJ, Canaday DH. Differential CD4+ T-Cell Cytokine and Cytotoxic Responses Between Reactivation and Latent Phases of Herpes Zoster Infection. Pathog Immun. 2023 Feb 17;7(2):171-188. doi: 10.20411/pai.v7i2.560. PMID: 36865570; PMCID: PMC9973729. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973729/

7. Zeng L, Feng S, Yao L, Zhao J, Zhang G. Disseminated Herpes Zoster with Decreased CD4 Counts in a HIV-Infected Patient. Clin Cosmet Investig Dermatol. 2023 Nov 2;16:3165-3170. doi: 10.2147/CCID.S429308. PMID: 37937316; PMCID: PMC10627087. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10627087/

8. Raha S, Mallick R, Basak S, Duttaroy AK. Is copper beneficial for COVID-19 patients? Med Hypotheses. 2020 Sep;142:109814. doi: 10.1016/j.mehy.2020.109814. Epub 2020 May 5. PMID: 32388476; PMCID: PMC7199671. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199671/

9. Raha S, Mallick R, Basak S, Duttaroy AK. Is copper beneficial for COVID-19 patients? Med Hypotheses. 2020 Sep;142:109814. doi: 10.1016/j.mehy.2020.109814. Epub 2020 May 5. PMID: 32388476; PMCID: PMC7199671. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199671/

10. EPA Registers Copper Surfaces for Residual Use Against Coronaviruses. EPA Press Office. An official website of the United States government. February 10, 2021. https://www.epa.gov/newsreleases/epa-registers-copper-surfaces-residual-use-against-coronavirus

11. EPA Registers Copper Surfaces for Residual Use Against Coronaviruses. EPA Press Office. An official website of the United States government. February 10, 2021. https://www.epa.gov/newsreleases/epa-registers-copper-surfaces-residual-use-against-coronavirus

12. Govind V, Bharadwaj S, Sai Ganesh MR, Vishnu J, Shankar KV, Shankar B, Rajesh R. Antiviral properties of copper and its alloys to inactivate covid-19 virus: a review. Biometals. 2021 Dec;34(6):1217-1235. doi: 10.1007/s10534-021-00339-4. Epub 2021 Aug 16. PMID: 34398357; PMCID: PMC8366152. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366152/

13. Theoharides TC, Conti P. Be aware of SARS-CoV-2 spike protein: There is more than meets the eye. J Biol Regul Homeost Agents. 2021 May-Jun;35(3):833-838. doi: 10.23812/THEO_EDIT_3_21. PMID: 34100279. https://pubmed.ncbi.nlm.nih.gov/34100279/

14. Bala S, Failla ML. Copper repletion restores the number and function of CD4 cells in copper-deficient rats. J Nutr. 1993 Jun;123(6):991-6. doi: 10.1093/jn/123.6.991. PMID: 8099369. https://pubmed.ncbi.nlm.nih.gov/099369/

15. Lelièvre P, Sancey L, Coll JL, Deniaud A, Busser B. The Multifaceted Roles of Copper in Cancer: A Trace Metal Element with Dysregulated Metabolism, but Also a Target or a Bullet for Therapy. Cancers (Basel). 2020 Dec 1;12(12):3594. doi: 10.3390/cancers12123594. PMID: 33271772; PMCID: PMC7760327.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760327/

16. Ge, E.J., Bush, A.I., Casini, A. et al. Connecting copper and cancer: from transition metal signalling to metalloplasia. Nat Rev Cancer 22, 102–113 (2022). https://doi.org/10.1038/s41568-021-00417-2

17. Tang X, Yan Z, Miao Y, Ha W, Li Z, Yang L, Mi D. Copper in cancer: from limiting nutrient to therapeutic target. Front Oncol. 2023 Jun 23;13:1209156. doi: 10.3389/fonc.2023.1209156. PMID: 37427098; PMCID: PMC10327296. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10327296/

18. Liu Y, Miao J. An Emerging Role of Defective Copper Metabolism in Heart Disease. Nutrients. 2022 Feb 7;14(3):700. doi: 10.3390/nu14030700. PMID: 35277059; PMCID: PMC8838622. https://pubmed.ncbi.nlm.nih.gov/35277059/#:~:text=Defects%20of%20copper%20homeostasis%20caused%20by%20perturbed%20regulation,failure%2C%20ischemic%20heart%20disease%2C%20and%20diabetes%20mellitus%20cardiomyopathy.

19. Hordyjewska A, Popiołek Ł, Kocot J. The many "faces" of copper in medicine and treatment. Biometals. 2014 Aug;27(4):611-21. doi: 10.1007/s10534-014-9736-5. Epub 2014 Apr 20. PMID: 24748564; PMCID: PMC4113679. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113679/

20. Chen, X., Cai, Q., Liang, R. et al. Copper homeostasis and copper-induced cell death in the pathogenesis of cardiovascular disease and therapeutic strategies. Cell Death Dis 14, 105 (2023). https://doi.org/10.1038/s41419-023-05639-w

21. Reid GM. Sudden infant death syndrome: congenital copper deficiency. Med Hypotheses. 1987 Oct;24(2):167-75. doi: 10.1016/0306-9877(87)90100-9. PMID: 3316946. https://pubmed.ncbi.nlm.nih.gov/3316946/

22. Erickson, M., Poklis, A., Gantner, G. et al. Tissue Mineral Levels in Victims of Sudden Infant Death Syndrome II. Essential Minerals: Copper, Zinc, Calcium, and Magnesium. Pediatr Res 17, 784–787 (1983). https://doi.org/10.1203/00006450-198310000-00003

23. DiNicolantonio JJ, Mangan D, O'Keefe JH. Copper deficiency may be a leading cause of ischaemic heart disease. Open Heart. 2018 Oct 8;5(2):e000784. doi: 10.1136/openhrt-2018-000784. PMID: 30364437; PMCID: PMC6196933. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196933/

24. Szewc M, Markiewicz-Gospodarek A, Górska A, Chilimoniuk Z, Rahnama M, Radzikowska-Buchner E, Strzelec-Pawelczak K, Bakiera J, Maciejewski R. The Role of Zinc and Copper in Platelet Activation and Pathophysiological Thrombus Formation in Patients with Pulmonary Embolism in the Course of SARS-CoV-2 Infection. Biology (Basel). 2022 May 14;11(5):752. doi: 10.3390/biology11050752. PMID: 35625480; PMCID: PMC9138256. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138256/

25. Hordyjewska A, Popiołek Ł, Kocot J. The many "faces" of copper in medicine and treatment. Biometals. 2014 Aug;27(4):611-21. doi: 10.1007/s10534-014-9736-5. Epub 2014 Apr 20. PMID: 24748564; PMCID: PMC4113679. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113679/

26. Wei J, Gianattasio KZ, Bennett EE, Stewart JD, Xu X, Park ES, Smith RL, Ying Q, Whitsel EA, Power MC. The Associations of Dietary Copper With Cognitive Outcomes. Am J Epidemiol. 2022 Jun 27;191(7):1202-1211. doi: 10.1093/aje/kwac040. PMID: 35238336; PMCID: PMC9890213. https://pubmed.ncbi.nlm.nih.gov/35238336/#:~:text=Higher%20intake%20of%20dietary%20copper%20from%20food%20was,fat%2C%20may%20increase%20the%20risk%20of%20cognitive%20impairment.

27. Agarwal, P., Ayton, S., Agrawal, S. et al. Brain copper may protect from cognitive decline and Alzheimer’s disease pathology: a community-based study. Mol Psychiatry 27, 4307–4313 (2022). https://doi.org/10.1038/s41380-022-01802-5

28. Patel R, Aschner M. Commonalities between Copper Neurotoxicity and Alzheimer's Disease. Toxics. 2021 Jan 7;9(1):4. doi: 10.3390/toxics9010004. PMID: 33430181; PMCID: PMC7825595. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825595/

29. Ejaz HW, Wang W, Lang M. Copper Toxicity Links to Pathogenesis of Alzheimer's Disease and Therapeutics Approaches. Int J Mol Sci. 2020 Oct 16;21(20):7660. doi: 10.3390/ijms21207660. PMID: 33081348; PMCID: PMC7589751. https://pubmed.ncbi.nlm.nih.gov/33081348/

30. Li X, Chen X, Gao X. Copper and cuproptosis: new therapeutic approaches for Alzheimer's disease. Front Aging Neurosci. 2023 Dec 19;15:1300405. doi: 10.3389/fnagi.2023.1300405. PMID: 38178962; PMCID: PMC10766373. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10766373/

31. Grossman JT, Ruiz S. Copper Deficiency Myeloneuropathy in Autoimmune Disease. Cureus. 2021 Jul 23;13(7):e16591. doi: 10.7759/cureus.16591. PMID: 34434682; PMCID: PMC8380469. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380469/

32. Lillo, Nicholas MD; Rosenfeld, Izabella MD; Costable, John MD; Storch, Ian DO. Copper Deficiency Induced Neuropathy: A Sticky Situation: 750. American Journal of Gastroenterology 104():p S278, October 2009. https://journals.lww.com/ajg/fulltext/2009/10003/copper_deficiency_induced_neuropathy__a_sticky.750.asp

33. Chami HA, Hall MAK. Copper Deficiency and Polyneuropathy: A Case Report. Cureus. 2022 Aug 22;14(8):e28261. doi: 10.7759/cureus.28261. PMID: 36158410; PMCID: PMC9491342. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491342/

34. Millhauser GL. Copper binding in the prion protein. Acc Chem Res. 2004 Feb;37(2):79-85. doi: 10.1021/ar0301678. PMID: 14967054; PMCID: PMC2907897. https://pubmed.ncbi.nlm.nih.gov/14967054/#:~:text=Copper%20binding%20in%20the%20prion%20protein%20A%20conformational,and%20the%20human%20afflictions%20kuru%20and%20Creutzfeldt-Jakob%20disease.

35. Salzano G, Giachin G, Legname G. Structural Consequences of Copper Binding to the Prion Protein. Cells. 2019 Jul 25;8(8):770. doi: 10.3390/cells8080770. PMID: 31349611; PMCID: PMC6721516. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721516/

36. Varela-Nallar L, González A, Inestrosa NC. Role of copper in prion diseases: deleterious or beneficial? Curr Pharm Des. 2006;12(20):2587-95. doi: 10.2174/138161206777698873. PMID: 16842180. https://pubmed.ncbi.nlm.nih.gov/16842180/

37. Rossi L, Lombardo MF, Ciriolo MR, Rotilio G. Mitochondrial dysfunction in neurodegenerative diseases associated with copper imbalance. Neurochem Res. 2004 Mar;29(3):493-504. doi: 10.1023/b:nere.0000014820.99232.8a. PMID: 15038597. https://pubmed.ncbi.nlm.nih.gov/15038597/#:~:text=Furthermore%2C%20copper%20interacts%20with%20the%20proteins%20that%20are,dysfunction%2C%20which%20is%20a%20common%20feature%20of%20neurodegeneration.

38. Rossi L, Lombardo MF, Ciriolo MR, Rotilio G. Mitochondrial dysfunction in neurodegenerative diseases associated with copper imbalance. Neurochem Res. 2004 Mar;29(3):493-504. doi: 10.1023/b:nere.0000014820.99232.8a. PMID: 15038597. https://pubmed.ncbi.nlm.nih.gov/15038597/#:~:text=Furthermore%2C%20copper%20interacts%20with%20the%20proteins%20that%20are,dysfunction%2C%20which%20is%20a%20common%20feature%20of%20neurodegeneration.

39. Ruiz LM, Libedinsky A, Elorza AA. Role of Copper on Mitochondrial Function and Metabolism. Front Mol Biosci. 2021 Aug 24;8:711227. doi: 10.3389/fmolb.2021.711227. PMID: 34504870; PMCID: PMC8421569. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421569/

40. Tassone G, Kola A, Valensin D, Pozzi C. Dynamic Interplay between Copper Toxicity and Mitochondrial Dysfunction in Alzheimer's Disease. Life (Basel). 2021 Apr 24;11(5):386. doi: 10.3390/life11050386. PMID: 33923275; PMCID: PMC8146034. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146034/

41. Ogórek M, Gąsior Ł, Pierzchała O, Daszkiewicz R, Lenartowicz M. Role of copper in the process of spermatogenesis. Postepy Hig Med Dosw (Online). 2017 Aug 9;71(0):663-683. doi: 10.5604/01.3001.0010.3846. PMID: 28791960. https://pubmed.ncbi.nlm.nih.gov/28791960/

42. Skoracka K, Ratajczak AE, Rychter AM, Dobrowolska A, Krela-Kaźmierczak I. Female Fertility and the Nutritional Approach: The Most Essential Aspects. Adv Nutr. 2021 Dec 1;12(6):2372-2386. doi: 10.1093/advances/nmab068. PMID: 34139003; PMCID: PMC8634384. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634384/

43. Herman S, Lipiński P, Ogórek M, Starzyński R, Grzmil P, Bednarz A, Lenartowicz M. Molecular Regulation of Copper Homeostasis in the Male Gonad during the Process of Spermatogenesis. Int J Mol Sci. 2020 Nov 28;21(23):9053. doi: 10.3390/ijms21239053. PMID: 33260507; PMCID: PMC7730223. https://pubmed.ncbi.nlm.nih.gov/33260507/

44. Bjorklund G. The role of zinc and copper in autism spectrum disorders. Acta Neurobiol Exp (Wars). 2013;73(2):225-36. doi: 10.55782/ane-2013-1932. PMID: 23823984. https://pubmed.ncbi.nlm.nih.gov/23823984/

45. Russo AJ. Increased Copper in Individuals with Autism Normalizes Post Zinc Therapy More Efficiently in Individuals with Concurrent GI Disease. Nutr Metab Insights. 2011 Sep 29;4:49-54. doi: 10.4137/NMI.S6827. PMID: 23946661; PMCID: PMC3738468. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738468/

46. Santos G, Borges JMP, Avila-Rodriguez M, Gaíno SB, Barreto GE, Rúbio ÉP, Aguiar RM, Galembeck E, Bromochenkel CB, de Oliveira DM. Copper and Neurotoxicity in Autism Spectrum Disorder. Curr Pharm Des. 2019;25(45):4747-4754. doi: 10.2174/1381612825666191217091939. PMID: 31845627. https://pubmed.ncbi.nlm.nih.gov/31845627/

47. Francis Z, Book G, Litvin C, Kalivas B. The COVID-19 Pandemic and Zinc-Induced Copper Deficiency: An Important Link. Am J Med. 2022 Aug;135(8):e290-e291. doi: 10.1016/j.amjmed.2022.03.008. Epub 2022 Apr 1. PMID: 35367442; PMCID: PMC8970610. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970610/

48. Arrieta F, Martinez-Vaello V, Bengoa N, Jiménez-Mendiguchia L, Rosillo M, de Pablo A, Voguel C, Martinez-Barros H, Pintor R, Belanger-Quintana A, Mateo R, Candela A, Botella-Carretero JI. Serum zinc and copper in people with COVID-19 and zinc supplementation in parenteral nutrition. Nutrition. 2021 Nov-Dec; 91-92:111467. doi: 10.1016/j.nut.2021.111467. Epub 2021 Aug 31. PMID: 34592694; PMCID: PMC8406548. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406548/

49. Skalny AV, Timashev PS, Aschner M, Aaseth J, Chernova LN, Belyaev VE, Grabeklis AR, Notova SV, Lobinski R, Tsatsakis A, Svistunov AA, Fomin VV, Tinkov AA, Glybochko PV. Serum Zinc, Copper, and Other Biometals Are Associated with COVID-19 Severity Markers. Metabolites. 2021 Apr 15;11(4):244. doi: 10.3390/metabo11040244. PMID: 33920813; PMCID: PMC8071197. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071197/

50. Francis Z, Book G, Litvin C, Kalivas B. The COVID-19 Pandemic and Zinc-Induced Copper Deficiency: An Important Link. Am J Med. 2022 Aug;135(8):e290-e291. doi: 10.1016/j.amjmed.2022.03.008. Epub 2022 Apr 1. PMID: 35367442; PMCID: PMC8970610. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970610/

51. George J. Brewer, Copper toxicity in Alzheimer's disease: Cognitive loss from ingestion of inorganic copper, Journal of Trace Elements in Medicine and Biology, Volume 26, Issues 2–3, 2012, Pages 89-92, ISSN 0946-672X, https://doi.org/10.1016/j.jtemb.2012.04.019