In addition to playing a role in Alzheimer’s dementia, (Koul, et al., 2023), cancer tumors also involve elevated or aberrant RAGE receptor activity - receptor for advanced glycation end products. (Riehl, et al., 2009) Elevated RAGE activity is also associated with a variety of lung conditions or premature lung development problems, (Winden et al., 2013), AND with the lung injury seen in COVID19 (the real cases, not the positive PCR test only or mild cases). The N portion of SARS-CoV-2/chimeric spike acts as a ligand to the RAGE receptor (Xia, et al., 2023) - activating it - and activation of it leads to promotion of cancer tumor cells. (Riehl, et al., 2009)
Zipping ahead to the relaxing part - a cup of medicinal or green or black tea may help calm RAGE receptor activity. More on the topic of the graphic is included later in this post.
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#Puntentional RAGE Reducing Teas & Phytonutrients - calm the inflammation and the irritable mood might get better too - but that is not the meaning of ‘RAGE’ = receptor for advanced glycation end products.
RAGE receptors and SARS-CoV-2 nucleocapsid protein (N-protein)
“Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein (N-protein) increases early in body fluids during infection and has recently been identified as a direct inducer for lung injury.” (Xia, et al., 2023)
And a recent post: Pomegranate peel extract or nobiletin from citrus peel, or curcumin, can inhibit Receptor for Advanced Glycation End Products (RAGE) receptors. Elevated RAGE activity is associated with inflammation and amyloidosis and risk of Alzheimer’s Dementia and Parkinson’s Disease. Inhibiting RAGE receptor activity is also nice because that type of receptor is being promoted by the chimeric spike of SARS-CoV-2 … which may be causing an increased amount of amyloidosis damage in younger ages of people. (Milton, 2023; Nyström and Hammarström, 2022; Roy, et al., 2021)
The N capsid is the green protein inside of the SARS-CoV-2 viral membrane. It can bind with amyloid proteins, the E, M, and Spike proteins can also. Accessory proteins produced by SARS-CoV-2 (info here, Redondo, et al, 2021), that additionally bind with amyloid include ORF6 and ORF10. (Figure 1, Milton, 2023)
. . . So, we are seeing cognitive decline in much younger age groups.
“Figure 1. SARS-CoV-2 amyloid formation and interactions. Extracellular SARS-CoV-2 virus enters cells via an interaction of the spike protein (S) with the cellular angiotensin-converting enzyme 2 (ACE2) receptor. Once inside cells, the mRNA is translated into a range of viral proteins including the structural spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins plus the accessory proteins ORF6 and ORF10, all of which can form amyloid fibrils that are likely to be generated intracellularly. The spike (S) protein can also bind Amyloid-ß and this is likely to occur where the Amyloid-ß fibrils are deposited extracellularly.” (Milton, 2023)
“Several investigations have shown that a raised AGEs serum level is linked to cognitive deterioration and the development of AD [48].
The AGE receptor (RAGE), which is present in the microglia and astrocytes among other body tissues, has been shown to be overexpressed in the brains of AD patients where it serves as a cell surface receptor and a transporter for Aβ [49].” (Koul, et al., 2023)
How does RAGE activation increase Cancer tumor cell growth? ….
Graphic description, image - see below:
“Figure 1. RAGE function in inflammation-associated carcinogenesis.
RAGE is expressed in all cell types implicated in tumour formation, including tumour cells, endothelial cells, myeloid cells, MDSCs, and lymphocytes.
Signalling pathways downstream of RAGE that are activated by the accumulation of its ligands (AGE, HMGB1, S100 proteins) regulate cellular interactions during neoplastic transformation and malignant progression:
(1) A pro-tumourigenic microenvironment is established by the secretion of pro-inflammatory cytokines such as TNFα, IL-1, and IL-6, and the production of RAGE ligands. [*Pomegranate/peel, niacin, and other phytonutrients help inhibit or reduce these inflammatory signaling chemicals.]
(2, 3) RAGE and RAGE ligands activate endothelial and myeloid cells resulting in the recruitment and accumulation of further myeloid cells, including MDSCs.
(4) MDSCs inhibit T and natural killer cells leading to T cell tolerance and impaired anti-tumour immunity.
(5) RAGE ligands and subsequent signalling [activation of the RAGE receptors by a variety of agonists leads to…] also fuel tumour cell proliferation and survival by autocrine and paracrine feed-back loops.
MDSC, myeloid derived suppressor cell; AGE, advanced glycation end products; HMGB1, high mobility group box-1; TNFα, tumour necrosis factor α, IL-1, interleukin-1; IL-6, interleukin-6.” (Riehl, et al., 2009) *Formatting changes added for emphasis.
The green T shaped lines mean a pathway is inhibited instead of increased, like an →, instead it blocks that direction --l. It is a Stop sign, or a Slow Down for Construction road sign. (Riehl, et al., 2009)
“RAGE function in inflammation-associated carcinogenesis. RAGE is expressed in all cell types implicated in tumour formation, including tumour cells, endothelial cells, myeloid cells, MDSCs, and lymphocytes. Signalling pathways downstream of RAGE that are activated by the accumulation of its ligands (AGE, HMGB1, S100 proteins) regulate cellular interactions during neoplastic transformation and malignant progression: (1) A pro-tumourigenic microenvironment is established by the secretion of pro-inflammatory cytokines such as TNFα, IL-1, and IL-6, and the production of RAGE ligands. (2, 3) RAGE and RAGE ligands activate endothelial and myeloid cells resulting in the recruitment and accumulation of further myeloid cells, including MDSCs. (4) MDSCs inhibit T and natural killer cells leading to T cell tolerance and impaired anti-tumour immunity. (5) RAGE ligands and subsequent signalling also fuel tumour cell proliferation and survival by autocrine and paracrine feed-back loops. MDSC, myeloid derived suppressor cell; AGE, advanced glycation end products; HMGB1, high mobility group box-1; TNFα, tumour necrosis factor α, IL-1, interleukin-1; IL-6, interleukin-6.” (Riehl, et al., 2009)
The agonists/ligands are listed in the center of the graphic in orange, and the RAGE receptors are in red in the graphic below shown on Lymphocyte (white blood cells), myeloid derived suppressor cell (MDSC) cells, Myeloid cells, Endothelium cells (line blood vessels), and on cancer tumor cells. The inflammatory agonists first activate the endothelium and myeloid cell RAGE receptors, which leads to an increase in the MDSC myeloid cells and inhibition of lymphocytes which normally would inhibit cancer tumor growth. (Riehl, et al., 2009)
Inflammation is needed to mobilize “myeloid derived cell populations” which include immune white blood cells and dendritic cells which support our brain neurons. Too much chronic inflammation becomes a bad thing though.
PAMPS - pathogen associated molecular patterns are proteins or other chemicals that our body is trained through cellular eons, to recognize as a problem that needs the attention of white blood cells - our cellular janitorial staff.
DAMPS - damage associated molecular patterns - the same story, except proteins and chemicals associated with cellular breakdown. It is toxic potentially to surrounding cells and needs to be cleaned up by white blood cells.
PAMPS and DAMPS can be ligands/agonists for RAGE receptors, or TLRs and NLRs - Toll-like or Nod-like receptors. (Liu et al., 2013)
We need a white blood response to fight infection (PAMPS) or clean up damaged cells (DAMPS), but an out-of-control number of white blood cells and edema/swelling can lead to more damage, (Liu et al., 2013), and amyloid protein tangles may develop as white blood cells can’t keep up with the janitorial job.
“Inflammation plays a critical role in host defense to invading microbial pathogens, and is also essential for the successful repair of tissue damage 1–4. Myeloid derived cell populations, such as monocytes, macrophages, dendritic cells, and granulocytes, that can recognize pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) present in microbial pathogens or as cellular molecules released by damaged tissues 1.
Binding of PAMPs or DAMPs to specific cell surface or intracellular receptors, such as Toll like receptors (TLRs), Nod like receptors (NLRs), and the receptor for advanced glycation endproducts (RAGE), in immune cells initiates a cascade of molecular events that leads to the production of pro-inflammatory cytokines, chemokines, reactive oxygen and nitrogen species, and antimicrobial peptides, as well as enhanced phagocytic activity 1–4. These signaling events are essential for the eradication of infection and rapid clearance of cell debris in damaged tissues 1–4. An appropriately orchestrated inflammatory response is also crucial for the subsequent activation of T lymphocytes and development of specific adaptive immunity 5.
Despite the benefits of inflammation in the protection of host from exogenous and endogenous insults, untimely and/or unnecessarily high degrees of inflammation can cause host tissue damage 6.” (Liu et al., 2013)
So, how do we inhibit overactive RAGE receptors? in summary…
Step (1) - reduce causes of inflammation and reduce inflammatory cytokines and TNFα.
Step (2, 3) and (5) - inhibit RAGE receptor activity.
Pomegranate peel and other polyphenols or other phytonutrients and niacin would help by reducing the inflammatory cytokines “TNFα, IL-1, and IL-6” in (1) - the “pro-tumurogenic microenvironment”. Bitter tasting phytonutrients help by promoting GLP-1 in the gut which can reduce inflammation.
And pomegranate and citrus peel and curcumin are known to inhibit RAGE receptor activity, step (2, 3) and (5) in the graphic above. (Reddy, et al., 2023) Hispidin, from Phellinus linteus, a yellow bitter or astringent tasting mushroom used in Traditional Chinese Medicine, also has been shown to reduce RAGE receptor activity. (El-Far, et al., 2020) Bitter tastes can be active at bitter taste receptor sites throughout the body in therapeutic ways.
RAGE Reducing Teas & Phytonutrients - these aren’t the typical Stress and Relaxation type like Lavendar or Chamomile, but those help reduce inflammation too.
Catechins - Tea leaves, Pomegranate peel, and Raspberry leaves too!
Catechins in green or black tea are similar to catechins in pomegranate/peel, Goji berries or Sumac spice which have hydrolysable tannins including gallotannins and ellagitannins. Pomegranate peel, Sumac and Goji berries can be used for hot beverages or Structured water style Suntea. (Brave AI summary/Goji Berry drinks)
Red raspberries have a much smaller amount of similar catechins, but raspberry leaves are a good source (Wu, et al., 2022) and are a traditional medicinal tea for use during pregnancy and lactation. Various review articles state raspberry leaf tea during pregnancy or lactation doesn’t show much efficacy for helping labor and delivery, or for increasing milk supply, but my midwife had recommended it simply as a nutritious tea.
Raspberry Leaf tea does show anti-inflammatory benefits and has nutritional content. Berry leaves of varied types are helpful and traditionally were used against the common cold, diabetes, inflammation and eye problems. (Ferlemi, et al., 2016) A patient forum has a testimonial for use of Raspberry leaf tea for dry eye symptoms. (forum.dryeyezone.com//our-dry-eye-triumphs/18206-the-only-thing-that-helps-is-raspberry-leaf-tea-but-it-works) Aside: The delphinidin, anthocyanidins, have been shown to be helpful for dry eye conditions in other studies.
Harvest your raspberry or other berry leaves for use fresh or to dry, after flowering or later in the summer or early fall, prior to November. The tannin content increases during the summer but then decreases in later autumn. (Ferlemi, et al., 2016)
“Berry leaves are byproducts of berry cultivation; their traditional therapeutic use against several diseases, such as the common cold, inflammation, diabetes, and ocular dysfunction, has been almost forgotten nowadays.” […]
“The main bioactive compounds in berry leaves are similar as in berry fruits, i.e., phenolic acids and esters, flavonols, anthocyanins, and procyanidins. The leaves are one of the richest sources of chlorogenic acid [an ester of caffeic acid and -quinic acid]. In various studies, these secondary metabolites have demonstrated antioxidant, anti-inflammatory, cardioprotective, and neuroprotective properties.” […]
“Berry phenolics represent a diverse group of compounds including phenolic acids (hydroxybenzoic and hydroxycinnamic acids, and their derivatives), flavonoids, such as flavonols, flavanols, and anthocyanins, and tannins (gallotannins and ellagitannins), divided into condensed tannins (proanthocyanidins) and hydrolysable tannins.” […]
“The beneficial medicinal properties are attributed to the bioactive compounds of the leaves, which are mainly hydrolysable tannins [21]. Gudej [24] reported that tannin concentration in the dried raspberry leaf ranges from 2.6% to 6.9% (w/w) and that the principle compounds are ellagic acids. Additional ellagitannins that have been identified in these leaves are the dimers sanguiin H-6 (13) and H-10, and the trimers lambertianin D and lambertianin C, as well as methyl gallate [19,21].” (Ferlemi, et al., 2016)
Curcumin in Turmeric and Golden Milk - Haldi Doodh
Curcumin would be in curries, or in Golden Milk, a traditional drink made in India with yellow turmeric root powder. Curcumin is a Vitamin D receptor agonist. Caution for colitis or Irritable Bowel type conditions as it acts as a TRP channel activator and may trigger symptoms.
Golden Milk: “Haldi Doodh (haldi=turmeric and doodh=milk)” Traditionally it might be made only with turmeric and milk for a mild beverage for children. It is called Masala Haldi Doodh when more spices are added to the simmering liquid. (cookwithmanali.com/golden-milk-masala-haldi-doodh/)
Ingredients
2 1/2 cups milk 20 oz, use milk of choice
3/4 teaspoon ground turmeric
4 green cardamom pods slightly crushed
1/2 inch ginger cut into thin slices
5-6 whole black peppercorns
1 inch cinnamon stick
1 tablespoon sweetener of choice sugar, maple syrup, honey, adjust to taste
or a dry spice blend can be used: Haldi Doodh Masala - blend one teaspoon of the spice mix with 1 cup of milk of your choice. Coconut milk may be used in the traditional beverage. The Masala/blend by diasporaco.com includes turmeric, ginger, cinnamon, cardamom, and black pepper, as used in the recipe above. It would be warming with a little kick. Served as a warm beverage, creamy like a rich hot chocolate.
Reduce other stressors and sources of inflammation in diet, environment and lifestyle.
Reducing any sources of inflammation in your diet, environment, or lifestyle would also help put out fires before they are started (reducing (1)) - less oxidative stress chemicals would be produced if your life has less stress. The simple, but hard math of life.
»> “Any sources of inflammation” includes emotional or physical stress, infection, chronic illness, and EMF, blue light screens in the evening or too much, loud noise, bad air, water, or food, or other environmental stressors. It also includes personal food sensitivities, allergens, or chimeric spike. Medications are frequently a source of increased inflammation due to depletion of mitochondrial support nutrients or harm to mitochondria in other ways.
Reducing stress, reduces AGEs production and RAGE receptor activity.
Reducing stressors of any type is also going to help reduce production of AGEs - glycated proteins which are also ligands/agonists of RAGE receptors.
Reducing dietary AGEs in your diet would also help. Examples include the crispiness on barbecue or baked goods, or skillet- or deep-fried foods. High levels of AGEs are created during caramelization, delicious sugared-protein.
Why care about microRNA? Plant polyphenols are anti-inflammatory through regulation of microRNA levels.
MicroRNA are short, non-coding sections of RNA, which control whether a messenger, mRNA, will be broken down, or made into a protein. - So, they are more in charge of gene expression than the gene itself, and plant phytonutrients can up or down-regulate microRNA in ways that promote reduced oxidative stress. The plant doesn’t have to think about putting on a sunhat, its phytonutrients will modify the chemistry to adjust for brighter sunlight, possibly by closing leaves to reduce moisture loss. Flowers may open on a sunny day, but stay closed on a chilly spring morning. It isn’t because the flower is checking the weather ap on its cellphone.
“MicroRNAs (miRNAs, miRs) are short, endogenously initiated, non-coding RNAs that bind to target mRNAs, leading to the degradation or translational suppression of respective mRNAs. They have been reported as key players in physiological processes like differentiation, cellular proliferation, development, and apoptosis. They have gained importance as gene expression regulators in the immune system. They control antibody production and release various inflammatory mediators. Abnormal expression and functioning of miRNA in the immune system is linked to various diseases like inflammatory disorders, allergic diseases, cancers etc. As compared to the average human genome, miRNA targets the genes of immune system quite differently. miRNA appeared to regulate the responses related to both acquired and innate immunity of the humans. Several miRNAs importantly regulate the transcription and even, dysregulation of inflammation-related mediators. Many miRNAs are either upregulated or downregulated in various inflammatory and infectious diseases. Hence, modifying or targeting the expression of miRNAs might serve as a novel strategy for the diagnosis, prevention, and treatment of various inflammatory and infectious conditions.” (Chandan, et al., 2020)
MicroRNA can signal cells to do things, in distant parts of the body or in nearby cells - autocrine or paracrine signaling. They can also potentially do things in other genetically similar people via exosomes, pheromones are a subtype of exosomes.
“Numerous studies have demonstrated that miRNAs can be released into extracellular fluids. Extracellular miRNAs can be used as biomarkers for a variety of diseases. These studies have been extensively reviewed (113–115) and therefore will not be discussed here. The extracellular miRNAs can be delivered to target cells and they may act as autocrine, paracrine, and/or endocrine regulators to modulate cellular activities (116). In this regard, miRNAs have hormone-like activities.” […] “Two populations of extracellular miRNAs exist in biological fluids. One can be found in vesicles such as exosomes, microvesicles, and apoptotic bodies (116, 120) while the other is associated with proteins, especially AGO2 (120, 125).” (O’Brien, et al., 2018)
Disclaimer: This information is being provided for educational purposes within the guidelines of Fair Use and is not intended to provide individual health care guidance.
Reference List
(Chandan, et al., 2020) Chandan K, Gupta M, Sarwat M. Role of Host and Pathogen-Derived MicroRNAs in Immune Regulation During Infectious and Inflammatory Diseases. Front Immunol. 2020 Jan 24;10:3081. doi: 10.3389/fimmu.2019.03081. PMID: 32038627; PMCID: PMC6992578. https://pmc.ncbi.nlm.nih.gov/articles/PMC6992578/
(El-Far, et al., 2020) El-Far AH, Sroga G, Jaouni SKA, Mousa SA. Role and Mechanisms of RAGE-Ligand Complexes and RAGE-Inhibitors in Cancer Progression. Int J Mol Sci. 2020 May 20;21(10):3613. doi: 10.3390/ijms21103613. PMID: 32443845; PMCID: PMC7279268. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279268/
(Ferlemi, et al., 2016) Ferlemi AV, Lamari FN. Berry Leaves: An Alternative Source of Bioactive Natural Products of Nutritional and Medicinal Value. Antioxidants (Basel). 2016 Jun 1;5(2):17. doi: 10.3390/antiox5020017. PMID: 27258314; PMCID: PMC4931538. https://pmc.ncbi.nlm.nih.gov/articles/PMC4931538/
(Liu et al., 2013). Liu G, Abraham E. MicroRNAs in immune response and macrophage polarization. Arterioscler Thromb Vasc Biol. 2013 Feb;33(2):170-7. doi: 10.1161/ATVBAHA.112.300068. PMID: 23325473; PMCID: PMC3549532. https://pmc.ncbi.nlm.nih.gov/articles/PMC3549532/
(O’Brien, et al., 2018) O'Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front Endocrinol (Lausanne). 2018 Aug 3;9:402. doi: 10.3389/fendo.2018.00402. PMID: 30123182; PMCID: PMC6085463. https://pmc.ncbi.nlm.nih.gov/articles/PMC6085463/
(Winden et al., 2013). Winden DR, Ferguson NT, Bukey BR, Geyer AJ, Wright AJ, Jergensen ZR, Robinson AB, Stogsdill JA, Reynolds PR. Conditional over-expression of RAGE by embryonic alveolar epithelium compromises the respiratory membrane and impairs endothelial cell differentiation. Respir Res. 2013 Oct 17;14(1):108. doi: 10.1186/1465-9921-14-108. PMID: 24134692; PMCID: PMC3853184. https://pmc.ncbi.nlm.nih.gov/articles/PMC3853184/
(Wu, et al., 2022) Wu, L., Yang, J., Wang, C., Li, N.. Liu, Y., Duan, A., Wang, T., Chemical compositions of raspberry leaves influenced by growth season, cultivars and leaf position, Scientia Horticulturae, Vol 304, 2022, 111349, ISSN 0304-4238, https://doi.org/10.1016/j.scienta.2022.111349. https://www.sciencedirect.com/science/article/pii/S0304423822004708
(Xia, et al., 2023) Xia J, Wang J, Ying L, Huang R, Zhang K, Zhang R, Tang W, Xu Q, Lai D, Zhang Y, Hu Y, Zhang X, Zang R, Fan J, Shu Q, Xu J. RAGE Is a Receptor for SARS-CoV-2 N Protein and Mediates N Protein-induced Acute Lung Injury. Am J Respir Cell Mol Biol. 2023 Nov;69(5):508-520. doi: 10.1165/rcmb.2022-0351OC. PMID: 37478333; PMCID: PMC10633841. https://pmc.ncbi.nlm.nih.gov/articles/PMC10633841/
Great article! I was wondering if you've done research on Melatonin and RAGE. Melatonin attenuates RAGE and retoinoid toxicity.