COVID-19 and iron dysregulation: distant sequence similarity between hepcidin and the novel coronavirus spike glycoprotein

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Background

The spike protein is a product of gain of function research, it's a bioweapon with many pathogenic sequences encoded, including mimicry of the main regulator of iron. Did bats mate with pangolins, snakes, puffer fish and half an ecosystem of organisms? Or as they said on Raiders of the Lost Ark: “…it is something that Man was not meant to disturb. Death has always surrounded it. It is not of this earth.”

Free iron is oxidising, highly toxic and is implicated in early stage oncogenesis via gene silencing (methylation) as well as hypoxia and a many other consequential pathologies.

“DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription.”

https://en.m.wikipedia.org/wiki/DNA_methylation

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COVID-19 and iron dysregulation: distant sequence similarity between hepcidin and the novel coronavirus spike glycoprotein (2020)

"Although this is a ‘distant’ and limited sequence similarity, it cannot be attributed to ‘chance’. The search that found hepcidin did not reveal a range of similarities with other teleost proteins. Moreover, there are many cysteine-rich protein sequences in teleosts and vertebrates in general, yet this similarity to the hepcidin gene family (not merely a one-off sequence) was unique and specific. How or why this similarity arose is then a separate, and potential follow-up, question.

The Hepcidin protein

Hepcidin is a small peptide hormone that was discovered in 2000/2001 [7, 63, 69, 96, 102], and initially named LEAP-1 (liver-expressed antimicrobial peptide). It has an antiparallel beta-sheet fold and contains four disulfide bonds, and is involved in iron trafficking and the host’s response to infection [34]. In fact, it has been remarked by a number of commentators that “hepcidin is to iron, what insulin is to glucose”

In fish species, one of the two hepcidin paralogs has been shown to potentially possess antimicrobial effects in innate immunity [78, 79]. Finally, hepcidin binds to and mediates the degradation of ferroportin (encoded by the SLC40A1 / FPN1 gene), the only known cellular iron exporter."

Comparison of select hepcidin and coronavirus spike protein sequences. a A multiple sequence alignment of the C-terminal region of a number of coronavirus spike proteins (encompassing portions of the putative transmembrane and cytoplasmic tail segments), four hepcidins and the SARS-CoV-2 envelope protein is presented.

Full paper:

https://biologydirect.biomedcentral.com/articles/10.1186/s13062-020-00275-2

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Elucidating of oxidative distress in COVID-19 and methods of its prevention (2021)

Abstract

The pandemic of SARS-CoV-2 stimulates significant efforts and approaches to understand its global spread. Although the recent introduction of the vaccine is a crucial prophylactic step, the effective treatment for SARS-CoV-2 is still undiscovered. An in-depth analysis of symptoms and clinical parameters, as well as molecular changes, is necessary to comprehend COVID-19 and propose a remedy for affected people to fight that disease.

The analysis of available clinical data and SARS-CoV-2 infection markers underlined the main pathogenic process in COVID-19 is cytokine storm and inflammation. That led us to suggest that the most important pathogenic feature of SARS-CoV-2 leading to COVID-19 is oxidative stress and cellular damage stimulated by iron, a source of Fenton reaction and its product hydroxyl radical (•OH), the most reactive ROS with t1/2–10−9s. Therefore we suggest some scavenging agents are a reasonable choice for overcoming its toxic effect and can be regarded as a treatment for the disease on the molecular level.

Keywords: SARS-CoV-2, COVID-19, Inflammation, Iron, Fenton reaction, Epigenetics, DNA methylation, Oxidative stress, ROS, 8-Oxo-guanosine, Lycopene

…ROS play a critical role in several physiological functions like proliferation and signaling pathways. In cellular (redox) systems, ROS level is tightly regulated to avoid excessive damage to cellular macromolecules. An imbalance of redox equilibrium leads to persistent oxidative stress favouring senescence, inflammation, and carcinogenesis. Reactive oxygen species cause a release of iron from storage in ferritin as well as damaging DNA, lipids, and proteins [Edeas et al., 2020]. Cellular damage involves reduced redox-active metal ions (ferrous and cuprous) that react with metabolically produced hydrogen peroxide H2O2. Hydroxyl radical (•OH) formed in the Fenton reaction is the site-specific product because of metal ions close to or bound to DNA .

Full paper:

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8106523/

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Iron Dysregulation in Human Cancer: Altered Metabolism, Biomarkers for Diagnosis, Prognosis, Monitoring and Rationale for Therapy (2020)

Abstract

Simple Summary

Iron is the more abundant metal ion in humans. It is essential for life as it has a role in various cellular processes involved, for instance, in cell metabolism and DNA synthesis. These functions are crucial for cell proliferation, and it is therefore not surprising that iron is accumulated in tumors. In this review, we describe normal and altered iron homeostasis mechanisms. We also provide a vision of iron-related proteins with altered expression in cancers and discuss their potential as diagnostic and/or prognostic biomarkers. Finally, we give an overview of therapeutic strategies acting on iron metabolism to fight against cancers.

…Numerous studies have shown that Fe contributes to carcinogenesis and metastatic processes. Altered Fe metabolism and cancer patients’ prognoses are linked.

…Hepcidin is an essential hormone for the regulation of Fe efflux and it contributes to the proliferation of cancer cells. Moreover, the expression and regulation of this hormone are variable within cancer tissues [114]. The concentration of hepcidin increases in many cancers such as myeloma, Hodgkin’s disease, breast, prostate, thyroid, and non-small-cell lung cancers (NSCLC), but also in other solid tumors [33,40,82,103,106,115]. Contrariwise, hepcidin concentrations are decreased in brain cancers, hepatocellular and renal cell carcinoma, and hepatocellular carcinoma [58,62,94,114]. Numerous studies have shown that the high expression of the hepcidin mRNA predicts poor prognosis and is associated with a metastatic profile.

Full paper:

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7761132/

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DNA methylation of hepatic iron sensing genes and the regulation of hepcidin expression (2018)

Abstract

Production of the iron regulatory peptide hepcidin is tightly controlled by a network of proteins in hepatocytes that sense levels of iron in the circulation (as diferric-transferrin) and in tissues (in ferritin). Human studies show high variability in the normal range of serum hepcidin levels. We have postulated that this may, in part, be related to inter-individual variability in the expression of genes in the iron sensing pathway, potentially governed by epigenetic factors. Here, we have investigated whether genes encoding hepatic iron sensing proteins and hepcidin are regulated by DNA methylation. Experiments were performed on two human hepatoma cell lines, HepG2 cells and Huh7 cells. Basal expression of TFR2 and HAMP was significantly lower in Huh7 cells compared with HepG2 cells. Analysis of bisulphite-converted DNA from Huh7 cells revealed partial methylation of TFR2 (alpha transcript), which could result in gene silencing. Demethylation using 5-aza-2’-deoxycitidine (AZA) increased TFR2 mRNA expression in Huh7. PCR analysis of bisulphite-converted HAMP promoter DNA, using methylation-specific primers, revealed no differences between cell lines. However, HAMP mRNA expression in Huh7 was increased by AZA treatment, suggesting that methylation of one or more iron sensing genes may indirectly influence HAMP expression. Our study provides evidence that DNA methylation might control expression of HAMP and other hepatic iron sensing genes, and indicates that epigenetic influences on iron homeostasis warrant further investigation.

Full paper:

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197863