Part 3 - microRNA, mRNA, CoV and Cancer; miR-21 and PPARa, RXR, palmitate or glucose versus polyphenols
Post too long for email, without the Reference list.
This document/post series is about a lengthy post by Genervter Bürger, ‘Annoyed Citizen’, in which Genervter gives an overview about microRNA and how it can play a role in cancer and chronic illness. The post is my source for the articles below by Sonia Elijah, and a lengthy reference list: Title translated into English, from the original German: The Road to Heaven or Hell - by Genervter Bürger = “Annoyed Citizen” (substack.com)
Part 1 microRNA, mRNA, CoV and cancer, (substack.com)
Part 1 is about Blotgate: What the ‘blots’ on a gel electrophoresis plate image provided by BioNTech/Pfizer suggest is that they may have committed fraud about the purity of their product and provided faked gel plate images. Fraudulent work would negate the liability free clause of their contracts.
See for the full article with images: Startling Evidence Suggests BioNTech and Pfizer Falsified Key Data: Part 1, by sonia_elijah, Feb 4, 2023, (trialsitenews.com), Excerpts are included later - see the article for images from the Pfizer documents though, and a quote of Jikkyleaks.
Part 2 - microRNA, mRNA, CoV injections & cancer; Baicalin resource by David Cowley and Johanna Deinert, (substack.com) *This has the initial Reference List.
Part 2 gets into the wrong length RNA question. See for the full article with images: Part 2: Startling Evidence Suggests BioNTech/Pfizer Falsified Key Data & Further Scandals (trialsitenews.com) Includes more images from the Pfizer documents and refers to work by Jikkyleaks and by Kevin McKernan regarding the DNA plasmids – see this post by Kevin McKernan, ‘Anandamide’ DNA-RNA hybrids, R-Loops and nuclease resistance of the mRNA vaccines (substack.com). The post gets technical, explaining why the DNA may be difficult to remove from the RNA for the CoV jabs. Being more temperature resistant may make the separation more difficult. Excerpt:
“Keep in mind your cells are processing R-Loop all the time. Every gene that gets expressed generates these, however these [modifiedRNA] modRNAs are not ordinary genes. As we have shown, they stall nucleases, they are quadruplex G dense and the 801 m1Ψs is not something the cell has ever seen before. m1Ψ is usually at 0.2-0.6% in human mRNA. The vaccine mRNA is 100% m1Ψ. [pseudouridine]
Why does m1Ψ matter in the world of R-Loops and RNA-DNA hybrids?
There is an important paper from Callum Parr et al. on the changes in melting temperature with the introduction of m1Ψ.” - Kevin McKernan, ‘Anandamide’, Nepetalactone Newsletter, Read more: DNA-RNA hybrids, R-Loops and nuclease resistance of the mRNA vaccines (substack.com).
Link to an article with more detail about LNPs, the DNA plasmids that were found and the associated cancer risk. Cancer & plasmids, tutorial by Christie Grace, biotech specialist. (substack.com) The article directly: Adverse Events (RNA/DNA/LNP Jabs) Due to Net Charge (Zeta Potential) on the LNP, RNA Fragments, Other Charged Particles, Lipid Properties, DNA Lipoplexes, the Spike Protein, and Protein Misfolding (substack.com)
Annoyed Citizen highlights the quality issues in the Part 1 article by Sonia Eliah – what may be the impact of having such a large error rate in the chimeric spike RNA? Almost half are admitted to being wrong – and the rules were just changed to get the approval through.
"A document from a crucial November 26, 2020 meeting between the EMA and Pfizer/BioNTech revealed the alarming fact that this "main objection" was "resolved" by simply lowering the standard to 50%, even though Pfizer claimed: "The efficacy of the drug depends on the expression of the RNA delivered, which requires a sufficiently intact RNA molecule." In addition, the set value was well below the minimum threshold of 70% required by Acuitas Therapeutics." Startling Evidence Suggests BioNTech and Pfizer Falsified Key Data: Part 1, by sonia_elijah, Feb 4, 2023, (trialsitenews.com),
And points out this article about microRNA 21 and its role in cardiovascular illness when up or down regulated, and in other diseases: “Moreover, studies have observed that miR-21 expression is important in other diseases, such as cancer (Bonci, 2010), kidney fibrosis (Chau et al., 2012), metabolic syndrome (Calo et al., 2016), and asthma (Kim et al., 2017).” (Dai, et al, 2020)
DNA plasmids are important, states Annoyed Citizen, but the RNA fragments are also of interest – what are they? How long are they? What might they produce if a ribosome can read them? Or might fragments be smaller and have microRNA effects? We don’t really know. Any research being done is happening independently with limited funding sources. As Kevin McKernan pointed out, (quotes in the part 2 article by Sonia Elijah), a lot more gene sequencing to find out what the fragments were should already have been done.
We do know CoV mRNA injections can have an aging effect on Horvath epigenetic clock estimates of a person’s biological age. (Pang, et al., 2022)
“Complementary longitudinal epigenetic clock analyses of 36 participants prior to and following Pfizer and Moderna mRNA-based COVID-19 vaccination revealed that vaccination significantly reduced principal component-based Horvath epigenetic clock estimates in people over 50 by an average of 3.91 years for those who received Moderna.” (Pang, et al., 2022)
MicroRNA are important regulators of protein production by breaking down mRNA to prevent protein transcription, but also by causing epigenetic changes in genes. MicroRNA, miR-26, miR-29, and miR-203, may cause epigenetic changes that lead to malignant cancer promoting changes. (Schoof, et al., 2015)
"Taken together, these data suggest that epigenetic changes that occur early during malignant transformation may be due to the modulation of miR-26, miR-29, and miR-203 and the resulting effects on key genes involved in the epigenetic machinery." (Schoof, et al., 2015)
mRNA, microRNA and long non-coding RNA – roles and differences.
Messenger RNA vary in length, matching the length of the gene encoding the protein. mRNA are regulated by smaller microRNA which can tag the mRNA for destruction. Long non-coding RNA also have regulatory roles that are less well understood than that of microRNA which is quite complex and still being studied too. MicroRNA can target many or a few mRNA. Dai, et al. shared web resources for data on what mRNA might be targeted by a miRNA: “TABLE 1. Useful web links for miRNA target prediction.” (Dai, et al, 2020)
“Furthermore, conventionally, miRNAs always bind to the 3′ UTR of their target mRNAs. However, in recent years, it has been reported that miRNAs could also bind to the CDS, promoter, and 5′ UTR regions of the target genes (Iwakawa and Tomari, 2013; Li et al., 2019).” (Dai, et al, 2020)
mRNA – messenger RNA is used to transcribe a protein by ribosomes. The length varies with the length of the completed protein. An average is in the range of 500-2000 nucleotide pairs.
MicroRNA – are short lengths of RNA, “(21–25 nts)” (Dai, et al, 2020) and act as regulators of mRNA and can prevent a protein from being made by the mRNA by causing the mRNA to be broken down. An overview video: Gene Silencing by microRNA, Katharina Petsche, (Youtube); Biogenesis of miRNAs and mode of action, QIAGEN, (Youtube); This video shows a real time simulation of an RNA being made from a DNA and then being made into a protein by a ribosome. DNA and RNA transcription video - real time DNA encoding protein, ljcp2010777, (Youtube).
siRNA – Small interfering RNA are also short and can block mRNA protein production similarly to microRNA. See: RNA interference (RNAi) Animation || miRNA || siRNA || mRNA regulation, Rethink Biology, (Youtube)
lncCode – Long non-coding RNA are typically over 200 nucleotides in length and do not code for a protein. The function is largely unknown but seem involved in regulatory roles over gene transcription and play a role in cancer and other chronic diseases. Visualize the Fascinating Roles of lncRNA, Bio-Rad Laboratories, (Youtube).
Up or down-regulation of miR-21 is seen in different types of cardiac or other health conditions. (Dai, et al, 2020) Like much of life, we need just the right amount of activity – not too much or too little.
Dai, et al, suggest that the difference in miR-21 expression may be due to different levels of excess glucose versus excess fats in a health condition. High glucose may increase miR-21, while palmitate led to decreased expression of the microRNA. (Dai, et al, 2020)
“The reason for the varied observations might be attributed to the fact that, although high glucose and high fat contribute to the etiology of diabetic cardiomyopathy, different sources have varied effects on miR-21 expression, which could exert diverse functions in multiple cell types. Liu et al. (2014) observed that high glucose increased the levels of miR-21, whereas Dai et al. (2018) and Zhou et al. (2018) observed that miR-21 expression decreased in response to palmitate.” (Dai, et al, 2020)
Palmitate is a 16-carbon chain saturated fat and is the most common saturated lipid seen in animals, plants and microorganisms. Within human health the level of palmitate is kept within a certain range in normal health which is generally not affected by dietary intake of palmitate as we can make it if the diet is low. However, excess may be produced by the body in response to a diet with excessive total calories (weight gaining) and high in carbohydrates along with a sedentary lifestyle. (Carta, et al., 2017) In other words, a Type 2 diabetes promoting diet and lifestyle might lead to excess palmitate and a confused body as to whether to make more (high glucose) or less miR-21 (high palmitate levels). (Dai, et al, 2020) ‘Might’ lead – speculative.
Background info: Digestion pathways are designed to switch back and forth between a focus on glycolysis when starches are prevalent or fats when food is scarce and body fat is being used or when the diet is high in the ratio of fats to starches. An excess of total saturated fat can keep the body and mitochondria in fat burning mode, without use of the citric acid cycle, which is fermentation and associated with cancer. Nuclear DNA methylation requires the cytoplasm and mitochondria to be performing the citric acid cycle so that it can also take place in the cell nucleus and provide methyl donors for the protection of DNA methylation. See this post: Houston, we have a problem. - by J Depew, R.D. (substack.com)
CoV era related info – microRNA may travel in exosomes to affect cells in other areas.
MicroRNA 21 can affect nearby cells by traveling in exosomes - paracrine signaling among groups of cells. (Dai, et al, 2020)
“Interestingly, exosomal miR-21 participated in angiogenesis (Wang et al., 2017), cell proliferation (Xiao et al., 2016), cardiac remodeling, and metabolic regulation via the paracrine signaling networks in the target cells as well (Luther et al., 2018).” (Dai, et al, 2020)
The article by Dai, et al, includes a disturbing pre CoV finding regarding viral myocarditis – only 60% of pediatric patients survived for ten years. (Towbin et al., 2006, cited by Dai, et al, 2020)
“Chronic inflammation of the heart tissue caused by the viral infection (principally by the coxsackievirus, HIV, and adenovirus hepatitis virus) is termed viral myocarditis (VMC) (Pollack et al., 2015; Fung et al., 2016; Wang Y. et al., 2018). Only 60% of pediatric patients with acute myocarditis survived for 10 years (Towbin et al., 2006), and 9% of patients suffered from dilated cardiomyopathy (DCM), and 12% of young adults died in a short interval following the onset of VMC (Fabre and Sheppard, 2006).” (Dai, et al, 2020)
Phytonutrients are frequently modulators – correcting imbalance whichever direction is needed.
Dai, et al, also mention that the ERK-MAPK pathway is affected by miR-21, (Dai, et al, 2020), which may suggest why pomegranate peel can be so helpful for heart health – it has modulatory effects over the ERK-MAPK pathway. (Rasheed, Akhtar, Haqi, 2010) Wikipedia: mitogen-activated protein kinases (MAPKs), originally called extracellular signal-regulated kinases (ERKs).
“miR-21 activates the ERK-MAPK pathway via the inhibition of SPRY1 and mediates the structural and functional deterioration of cardiac function (Thum et al., 2008).” (Dai, et al, 2020)
And the MAPK/ERK signaling pathway may have regulatory control over miRNA machinery in general, (Paroo, Ye, Chen, Liu, 2009), which also suggests why pomegranate peel or other polyphenols can help so many different health concerns, as they can modulate or inhibit MAPK activation. (Rasheed, Akhtar, Haqi, 2010)
“Taken together, these studies suggest that the MAPK/Erk signaling pathway regulates the miRNA machinery and suggests a general principle in which signaling systems target the miRNA signaling pathway to achieve biological responses." (Paroo, Ye, Chen, Liu, 2009)
Pomegranate (caffeic acid, catechin, anthocyanin, quercetin) and citrus peel (hesperidin, naringenin, quercetin) can help in varied ways and other phytonutrients like baicalin (Cowley, Deinert, 2022) and other functional foods like medicinal mushrooms or turmeric (curcumin), rosemary, and oregano, may also help as modulators of microRNA – helping to correct a misbalance, whether there is too much or too little expression is occurring.
The MAPK signaling pathway was modulated by all nine polyphenols that were screened in a study by Milenkovic, et al., which assessed the modulation of miRNA by the polyphenols. The polyphenols, from different plants, all affected similar microRNA and pathways in anti-inflammatory ways. What were the tested polyphenols? Drumroll… the phenolic acids: caffeic and ferulic acid; and the flavonoids: quercetin, anthocyanin, catechin, proanthocyanin, hesperidin, and naringenin; and curcumin. The animals were supplemented with one of the polyphenols for a two-week time period. (Milenkovic, et al., 2012)
And the five microRNA? Three miRNAS were observed to be down-regulated by all nine tested polyphenols (mmu-miR-30c-1*, mmu-miR-374* and mmu-miR-497b*) and two miRNAs were found to be up-regulated (mmu-miR-291b-5p and mmu-miR-296-5p). See: (Table 2, Milenkovic, et al., 2012)
Note, that while five were affected by each of the nine polyphenols, each polyphenol up or down regulated many miRNA. Five were found to overlap for all of them. Caffeic acid modulated the fewest at 29 miRNA changes, and hesperidin the most with 97 miRNAs differentially expressed. See: (Table 1, Milenkovic, et al., 2012) The apo e -/- mice had 119 miRNAs with a difference in up or down regulation than the control mice (27 down- and 92 up-regulated).
The study was done with apoE deficient mice and many imbalances in microRNA due to the apoE difference were corrected – modulated up or down as needed to restore more normal function. (Figure 3, CC-BY the authors Milenkovic, et al., 2012) See the tallest column, second group, “Cell signalling pathways”:
This explains why pomegranate is so helpful against cancer and misfolded protein conditions, and pain.
Mitogen-activated protein kinase (MAPK) is inhibited by phytonutrients in pomegranate peel extract (PPE) by the regulation of Fox03, which would decrease unwanted phosphorylation of proteins, observed in an animal-based study in which PPE reduced ototoxicity caused by amikacin (AMK). (Liu, et al, 2017)
*Excerpts about the (Milenkovic, et al., 2012) article are from this post, there is more about the paper’s findings and it introduces post-translational modification of proteins which the kinases do – and that can cause hypersensitivity to pain or other negative health issues like cancer. microRNA are the real regulators of gene transcription. (substack.com)
The Peroxisome proliferator-activated receptor α (PPARα) can be down-regulated by miR-21 – and that is a big deal as it affects gene transcription of many proteins involved in fat digestion and the innate immune response.
miRNA 21 also can down regulate the Peroxisome proliferator-activated receptor α (PPARα), which has gene transcription power over fat metabolism within the liver and body, (Dai, et al, 2020); and PPARα is involved in innate immune function and affects trauma response symptoms of pain, swelling, and redness at the site of an injury or systemically. Mast cell degranulation and histamine are involved. (Grabacka, 2021)
“miR-21-dependent PPARα downregulation could affect fatty acid oxidation and trigger steatosis in hepatocytes (Loyer et al., 2016) as well as mediate kidney injury and fibrosis in epithelial cells (Chau et al., 2012). Meanwhile, miR-21 targeted PPARα resulted in increased inflammation owing to the ECs in the heart.” (Dai, et al, 2020)
Innate Immune Response – a mini-review: “The three main steps of the innate response are (1) building of a physical and chemical barrier, (2) recognition of foreign invaders and distinguishing from ‘self’ structural elements, and (3) phagocytosis and production of cytotoxic compounds that help to destroy engulfed particles or are released to damage objects too large to be phagocytosed. For example, various epithelial cells not only form a physical barrier of epithelium protecting the body from the external environment but also secrete hydrolytic enzymes and alarmins such as various antimicrobial peptides (AMPs) [10].” (Grabacka, 2021)
Peroxisome proliferator-activated receptor α (PPARα): “In this review, we focus on peroxisome proliferator-activated receptor alpha (PPARα), which is particularly responsible for the regulation of fatty-acid catabolism and ketogenesis [39,40], also in addition to being deeply involved in the modulation of innate immunity responses.” […]
“Interestingly, in addition to the tissues with a high rate of fatty-acid catabolism, such as the liver, cardiac muscle, and kidneys, PPARα is generally expressed in CD45+ leukocytes [50], including numerous innate immune cell populations: basophils [51], eosinophils [52], monocytes and macrophages [30,53,54,55], Kupffer cells [56], Langerhans cells [57], osteoclasts [58], and microglia [59].” […]
“Transrepressive activity toward nuclear factor κB (NF-κB), activation protein (AP-1), and signal transducers and activators of transcription (STATs) is responsible for PPARα’s profound anti-inflammatory action.” (Grabacka, 2021)
“The classical PPARα targets include the genes encoding enzymes from the fatty-acid mitochondrial and peroxisomal β-oxidation (acyl-CoA dehydrogenases, acyl-CoA oxidases), ω-oxidation and ω-hydroxylation (cytochromes P450), and ketogenesis (3-hydroxy-3methylglutaryl-CoA synthase) [60,61,62].
Importantly, in addition to this canonical mode of action, PPARα is able to transrepress certain genes through at least three mechanisms [63]: (i) initiating protein–protein interactions and sequestration of coactivators that are common to PPARα and other pathways, (ii) cross-coupling of the PPARα/RXR complex with other transcription factors, which leads to mutual cross-inhibition of both participating proteins, and (iii) interference with signal-transducing proteins, i.e., where the PPARα/RXR complex inhibits phosphorylation of MAP-kinase cascade members.” (Grabacka, 2021)
To function as a gene transcription factor PPARα has a partner, the Retinoid X Receptor (RXR), (Grabacka, 2021) so lack of vitamin A or excess over-activation of retinoids may also affect function of PPARα and any genes affected by the transrepression mentioned in the previous quote: “ii) cross-coupling of the PPARα/RXR complex with other transcription factors, which leads to mutual cross-inhibition of both participating proteins.” (Grabacka, 2021)
“As a transcription factor, PPARα is involved in the activation of gene transcription, which is carried out by binding the heterodimer of PPARα and the pan-PPAR obligatory partner, retinoid X receptor (RXR), to consensus motifs in the target promoters. The active heterodimer is formed when both partners have their agonists bound.” (Grabacka, 2021)
PPARα agonists: “The most potent endogenous PPARα agonists include fatty acids and their derivatives: saturated stearic and palmitic acids, fatty acyl amides such as oleylethanolamide (OEA) and palmitoylethanolamide (PEA), LOX products such as 5-(S)-HETE and 8-(S)-HETE, and leukotriene B4 (LTB4) [41,42,43,44].”
RXR ligand: “There is the only one bona fide RXR ligand known so far, which is 9-cis-13,14-dihydroretinoic acid, successfully identified after many years of searching, whereas 9-cis-retinoic acid, frequently used experimentally, is one of the most potent pharmacological RXR agonists [45,46]. […] The structures of endogenous ligands, as well as the most important synthetic agonists and antagonists, are presented in Table 1.” (Grabacka, 2021)
That miR-21 affects PPARα is a big deal because it can affect so many other genes and it may be a curveball that a Retinoid over-activation problem - or alcoholism, may compound dysfunction of the PPARα transcription factor.
I think we learned something, but there is more to learn.
That was the first link in the reference list by Annoyed Citizen, plus my additions. There is a lot to unpack on the topic of microRNA, let alone mRNA, CoV and Cancer. Baby steps, we have a journey ahead of us.
Disclaimer: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.