Endoplasmic Reticulum stress, misfolded proteins, allosteric modulators and delphinidin.

...also, Histamine type H1 and NMDAR receptors.

Housekeeping notes - Thank you readers! and welcome new subscribers! The emailed post may be shorter than the full post. This one is currently 15 pages, at least that isn’t 17! (document version - Subsection links in the introduction are bookmarks that go to the document.) The emails will not get any updates to a post. The last post did get updates and is background or related to this post.

• Previous post, related background info: Nrf2 & NF-kB: 2 proteins to know.

Introduction: 

This article delves into the question of histamine excess common in Alzheimer’s, but often unrecognized, and how that might overlap with increasing risk for misfolded protein accumulation.

Misfolded protein accumulation begins in the Endoplasmic Reticulum (ER), where proteins are made and identified as wrong as needed. The problem is too much can cause stress from an overload of misfolded or wrong length proteins. When the ER is too overloaded with tagged proteins to be removed, coupling with mitochondria leads to apoptosis of the cell. (1) Misfolded proteins can cause misfolding of other proteins leading to larger tangles outside of the cell. A gene difference may cause the person to be making misfolded proteins in large quantities. (27) Subsection: Endoplasmic Reticulum & misfolded proteins.

The hippocampus is an early target in Alzheimer’s because it has more NMDA receptors (NMDARs) than average and excess dietary glutamate is common in modern life. It is an agonist of NMDARs, too much activation can lead to an influx of too much calcium leading to excitement. The seasonings can lead to addictive overeating as they are stimulating to the brain. Too much overactivity can lead to cell death. Subsection: Hippocampus has more NMDARs.

The accumulation of misfolded prion proteins also may increase NMDAR activity because their normal function includes down regulating the receptors. Subsection: Misfolded proteins & NMDAR down regulation.

Misfolded protein problems also seem to include mitochondrial dysfunction along with histamine excess leading to or correlated with NMDAR receptor overactivity.

NMDAR receptors are the link between Alzheimer’s misfolded protein damage and histamine excess seen in Alzheimer’s. The H1 histamine receptor can down regulate NMDAR activity but seems to use a different agonist than histamine to do so - a mystery to solve! Histamine excess would be activating H1 receptors in a way that could be symptomatic of seasonal allergies or worse histamine symptoms, while not providing the alternate agonist’s down regulation of NMDARs. 

Various NMDAR antagonists are known and some are used beneficially for Alzheimer’s or other neurocognitive conditions. Subsection: Phytonutrients that are antagonists of NMDARs. Antihistamines have been found useful for Alzheimer’s care and in Covid treatment. Histamine excess has been a common problem among people with LongCovid symptoms.

Allosteric modulators are among the types of chemicals that can act as modulators of NMDAR activity - increasing the channel being opened, while inhibiting the entry of calcium - allowing function without excess calcium intracellularly.

“This class of chemical probes we show regulates both channel gating and ionic selectivity, and thus establish a new precedent in ion channel biology that could allow the tuning of specific facets of NMDAR signaling that contribute to circuit function or are dysregulated in disease. For example, biased allosteric modulators that enhance NMDAR open probability while decreasing NMDAR permeability to Ca2+ the enhancement of NMDAR currents while protecting neurons from calcium-induced toxicity.” (10)

Subsection: Allosteric Modulators.

Dietary influences: Excess dietary glutamate and calcium can be risk factors, along with low magnesium, copper, inositol, (1), B6, and methyl folate. Adequate glycine is helpful while glyphosate residue can increase misfolded protein risks. Mitochondrial support nutrients and cofactors are needed.

Solutions for misfolded proteins also include allosteric modulators like delphinidin to help stabilize or modulate receptor function. Phytonutrient based solutions for histamine excess and/or NMDAR antagonists can help reduce over activity along with lifestyle factors - water, sunshine, exercise, sleep with black-out curtain level dark or eye cover and avoid EMF.

Fibrinolytics to help break down fibrotic build-up before it is excessive may be helpful in inflammatory conditions and may be critical in CoV care. It has been found that our white blood cells break down the chimeric spike into seven prion-like domains but our plasmin can not break them down further like other amyloid proteins. (28, 29) Serrapeptase, a silkworm fiber enzyme, may be helpful or others: nattokinase, bromelain, or lumbrokinase.

SubSections:

Endoplasmic Reticulum is our protein production cellular organelle and for ID-ing & removing misfolded proteins.

A review article (Arlier et al, 2017) regarding the role of Endoplasmic reticulum (ER) overload of misfolded proteins in reproductive disorders, male and female, also includes a good description of the process of making proteins and removing badly formed versions. (1) The cellular system focuses on production without error correction, instead the erroneous proteins are identified as wrong and removed for recycling of the amino acids.

Stages of the assembly line like cell organelle include identification of misfolded proteins or ones that are too short or too long for the goal product. If too much error filled proteins accumulate within the channels of the ER, it can cause oxidative stress for the organelle and eventually for the cell. (1)

“During the production of functionally effective proteins, several ER-specific molecular steps sense quantity and quality of synthesized proteins as well as proper folding into their native structures. During this process, excess accumulation of unfolded/misfolded proteins in the ER lumen results in ER stress, the homeostatic coping mechanism that activates an ER-specific adaptation program, (the unfolded protein response; UPR) to increase ER-associated degradation of structurally and/or functionally defective proteins, thus sustaining ER homeostasis.” (1)

If the cell cannot keep up with removal of the identified bad proteins, (adequate inositol, a B vitamin would be helpful) then the cell response leads to apoptosis, death and removal of the whole cell. The apoptosis action involves linking the ER to mitochondrial pathways. Two proteins work together in tagging bad proteins for removal: inositol-requiring enzyme 1 (IRE1) and glucose-regulated protein 78 (GRP78). ATF6 and PERK are two other proteins that may be used to label misfolded proteins in the ER. (1)

“However, if the primary stimulus that causes ER stress is either prolonged or severe, cell death primarily by apoptosis is induced [56,57,58], specifically by coupling of the ER with mitochondrial pathways [50] suggesting that the [unfolded protein response] UPR protects cells from mild stress, but can also initiate apoptosis if ER stress inducers are sustained and become intolerable (Figure 1B).” (1)

Accumulation of misfolded proteins can lead to Alzheimer’s dementia and Parkinson’s disease or prion disease. Excessive GRP78 is seen in some types of cancer cells leading to increased use of glucose. (1) Misfolded protein accumulation is also seen in some patients with autism. A gene difference is involved in one type which leads to a misfolded protein sequence being generated which leads to ER stress. (27)

“Impaired protein folding, as exemplified by increased mal-folded protein accumulation, is associated with neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, as well as prion protein diseases [42,43,44,45]. Furthermore, induction of GRP78 in multiple types of solid tumors is attributed to glucose starvation resulting from poor perfusion within tumors as well as hyper-metabolic characteristics of cancer cells that require much higher glucose utilization rates [18].”

So adequate glucose is also needed to remove misfolded proteins. General malnutrition is a risk factor for myelin degeneration. Genetic differences are more commonly seen in the study of Alzheimer’s and Parkinson’s regarding misfolded proteins, so a lack of other nutrients than glucose may be driving factors. Calorie excess with trace nutrient deficiencies may be likely in Alzheimer’s risk. Mitochondrial support nutrients and cofactors are likely needed as mitochondrial dysfunction is also an early indicator of risk in many neurodegenerative conditions.

Solutions - magnesium, water, moderate calorie intake, good sleep!

For apoptosis to work instead of having an accumulation of damaged cells, adequate magnesium is needed along with water, and potassium and sodium in balance. Calcium is needed but the modern diet and supplements tends to over provide it and the bones may release it during inflammation. Vitamin D and vitamin K/K2 are also needed for calcium balance. Inflammation leads to increased calcium loss from bone tissue and deposits of it in the cardiovascular system or in odd places like bone spurs or arthritic knuckles.

It also helps to not overeat, then the body will have the need, and the time, to remove cellular debris such as erroneous proteins. When we overeat or eat late in the evening, during sleep when clean-up should be occurring, the body has to work to store extra calories as fat instead.

Full range of motion exercise and sunshine during the day will help lymphatic flow and circadian changes. Good sleep quality for circadian cycle epigenetic changes to occur each night is also a need. Clean-up is a night time job - our sanitation crew can be hard at work, if we are sleeping well. It all becomes more difficult as we age, extra nutrient dense food choices are important as calorie needs are also reduced as we age.

“In young and healthy cells, the misfolded protein load is disposed of by protein quality control (PQC) systems. In aging cells and in cells from certain individuals with genetic diseases, the load may overwhelm the PQC capacity, resulting in accumulation of misfolded proteins. Dependent on the properties of the protein and the efficiency of the PQC systems, the accumulated protein may be degraded or assembled into toxic oligomers and aggregates.” (2)

The phrase “Toxic oligomers and aggregates” is referring to the misshapen proteins and clusters they form. The clumped proteins disrupt normal function in the surrounding cells and eventually lead to fibrotic scarring and cell death in the region of the tangle. In Alzheimer’s dementia the hippocampus is damaged sooner than other areas and that is why short term memory formation is early in lost skills - the hippocampus helps us with learning new things or just remembering where we set down our keys. Childhood memories are stored elsewhere and that is why they remain the longest if/as deterioration continues.

Solutions for preventing neurodegeneration -

• Inositol, magnesium, & other mitochondrial support nutrients and cofactors.

• Vitamin D3 and/or 15-30 minutes of sunshine or full spectrum light per day; blackout curtains or eye-cover at night. Avoid EMF it increases calcium channel activity and inflammatory risk.

Circadian cycle epigenetics are key to our growth and repair. Modern life tends to keep us at the daytime gene settings all the time, instead of switching to the Nrf2 focused genes each night as our natural design expects.

• Vitamin K2 and leafy green vegetables for K1.

• Phytonutrient rich produce, herbs, spices, teas, coffee - all can help promote Nrf2, inhibit NF-kB, and may interact in other ways to modulate immune function, reduce oxidative stress in the Endoplasmic Reticulum, or elsewhere.

• Moderate calorie intake, reduced carbohydrate balance (30% of calories from carbs instead of 45-55%, I recommend more fats to make up the difference rather than risk a protein overload on the kidneys), avoid late night eating.

• Water, full range movement, and aerobic exercise, if possible, to help lymphatic flow and toxin removal, and to prevent edema.

• Low histamine diet and avoid glutamate foods.

• Avoid alcohol in excess and certain medications may increase histamine excess: “alcohol and monoamine oxidase inhibitors” and “20% of Europeans” may be affected by their use of: “verapamil, clavulanic acid, chloroquine derivatives, acetylcysteine, amitriptyline, metamizole, and isoniazid.” (25) Alcohol and acetaldehydes also need the enzyme aldehyde dehydrogenase for breakdown, competing with histamine. (25)

• Have adequate methyl folate to breakdown histamine. Adequate copper to balance zinc intake is also needed, along with vitamin C and pyridoxine (B6) as they seem to be needed for the DAO enzyme that breaks down histamine. (25)

• Avoid high dose unmethylated folic acid or cyanocobalamin (standard form of B12 in supplements).

• Be aware that histamine excess can fluctuate with the menstrual cycle. “DAO activity also depends on the phase of the menstrual cycle [24].” (25)

Regarding methylation - needed for proper epigenetic control of our genes.

The unmethylyated forms of the B vitamins are not useful for people with methylation gene differences or possibly anyone who is more elderly or infirm/ill. They also are filling the puzzle box with way too many pieces that may fill spots in a chemical reaction but do not provide function - do not help it to the next step on the chemical pathway.

It can take many steps for our body to produce one molecule from other molecules - obtaining it from the diet, if possible, saves us energy even if we can make the molecule. Nucleotides are a good example - vegan diets are low in preformed nucleotides and could benefit from 2 teaspoons per day of (unfortified*) Nutritional Yeast Flakes. *Unfortified with the standard cyanocobalamin and folic acid which is hard to find and more expensive currently.

Hippocampus has more NMDARs than average so is at greater risk - excess dietary glutamate or calcium are also risk factors, and histamine via increased H1 receptor activity.

The hippocampus is targeted in part because of the extra NMDAR receptors, (17, viewable at 18), which need glutamate and glycine to be activated and can be inhibited by magnesium inside of the cell. Once activated the receptor is an ion channel that allows calcium, potassium and sodium to enter cells.

The modern diet tends to have an excess of glutamates and calcium, and may be low in potassium, magnesium, and possibly glycine. Glycine is an amino acid that was the backbone for synthesizing glyphosate. Content of glycine in our food may be affected by the substitution of glyphosate from herbicide use. More testing of foods would be ideal, but residue has been found in most oat and wheat products that were tested.

Magnesium inside of the cell can block the channel when the membrane is not depolarized and prevent the calcium entry. Too much calcium inside of a cell can cause overexcitement of cells and lead to cell death. Dead cells create cell debris that needs to be removed, increased white blood cells are called in to remove it. Too much of that activity can also lead to fibrotic scarring and regions of dead cells. Cell debris can cause oxidative stress on surrounding cells.

“The NMDAR is unique in that the opening of the channel pore requires binding of two different agonists –glutamate as well as glycine (3). The glutamate binding site resides on the NR2 subunits whereas the glycine binding site is located on the NR1 subunits (Figure 2A). The NMDAR ion channel is permeable to monovalent cations, including Na+ and K+, and divalent cations, most notably Ca2+. However, there is a binding site within the channel pore for Mg2+ and, at resting membrane potential, Mg2+ binds to this site largely blocking ion flow through the channel. When the membrane is depolarized, Mg2+ is expelled from the channel allowing for greatly enhanced passage of ions.” (8)

Excitotoxicity - excess glutamate can lead to excess calcium entry into cells with NMDAR receptors. This process has been linked to many chronic neurodegenerative conditions and acute ischemic stroke or Traumatic Brain Injury (TBI); “malignant gliomas (10)”.

“The initial focus on NMDARs was based on the finding that excitotoxicity, a pathological process where neuronal injury or death occurs due to high concentrations of glutamate, results predominantly from excessive NMDAR activity with increased inflow of Ca2+ through the NMDAR channel (8). This process has been implicated in both acute ischemic stroke and TBI. Glutamate excitotoxicity is also presumed to contribute, at least partly, to neuronal loss in chronic neurodegenerative conditions, including AD and other dementias, Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and possibly multiple sclerosis (MS) and prion disease.” (8)

Glutamate excess may also be involved in hyperexcitability issues which histamine excess also causes.

“Excessive NMDAR activity may also underlie neurological disorders characterized by hyperexcitability or sensitization of neurons, such as seizure disorders (8), neuropathic pain states (12), and some types of dyskinesias (13). In contrast, it has been proposed that underactivity of NMDARs may be associated with neurodevelopmental conditions, specifically schizophrenia (14).” (8)

The Histamine Type 1 Receptor (H1) modulates NMDAR receptor activity. Blocking the H1 receptor led to more NMDAR activity. Histamine itself did not increase or decrease NMDAR activity; it was the HI receptor activity that affected it in this study. (9) Histamine is an agonist of the H1 receptors and has been found to enhance NMDAR activity (22) but H1 Receptor activity may also have other agonists. (23) So some other agonist at the H1 receptors must down regulate the activity of the NMDAR receptors. Histamine excess would be activating them but possibly not in a way that led to down regulation of NMDAR activity.

There are four types of histamine receptors and the affinity for histamine is greater for H3 and H4 receptors than for H1 and H2 receptors which are more active in the brain. Hyperexcitability symptoms of histamine excess were not early in my personal years of undiagnosed problems with histamine. Migraines and seasonal allergies, eczema, were chronic problems though. I do have methylation gene differences and others. Some people may have differences in the DOA enzyme leading to histamine excess.

“The two classic histamine receptors, H1 receptor and H2 receptor, are well known as drug targets for allergy and gastric ulcer, respectively. These receptors have lower affinity for histamine than the more recently discovered H3 and H4 receptors. The H1 and H2 receptors are important postsynaptic receptors in the brain, and they mediate many of the central effects of histamine on, e.g., alertness and wakefulness.” (23)

Excess activity of the H1 receptors can lead to vascular dilation and edema, in the brain (17, viewable at 18) or elsewhere in the body. Seasonal allergy symptoms of runny nose and itchy dry eyes may also occur. (18) Quercetin and luteolin are flavonoids that can help reduce the effects of excess histamine. (24, 25)

Inositol can help.

“In addition, stimulation of the H1 receptor causes changes in vascular permeability, particularly the postcapillary venule as a result of endothelial cell contraction (Majno et al., 1968; Svensjo and Grega, 1986). Stimulation of histamine H1 receptor–induced contraction is mediated by inositol 1,4,5-triphosphate–induced mobilization of intracellular calcium (Morel et al., 1987).” (17, viewable at 18)

The H1 receptors - in the presence of excess histamine - can cause many symptoms in addition to seasonal allergies. Edema and vascular changes may occur in the heart, lungs and body. Pain and muscle spasms may be likely in the gut, elsewhere, or as presenting as migraines. Increased Th1 immune cell response also occurs.

“The following are the major consequences of H1 receptor stimulation:

■ Capillary and venous dilation, which can produce marked hypotension. In the skin, histamine contributes to the wheal-and-flare response; an axon reflex via H1 receptors is responsible for the spread of vasodilation or flare from the oedematous wheal.

■ Increased capillary permeability, which produces local oedema. This can lead to urticaria, angioedema and laryngeal oedema. The consequent loss of fluid from the circulating blood volume contributes to hypotension. [low blood pressure, tiredness, and poor concentration may be linked]

■ Smooth muscle contraction, especially in bronchioles (producing bronchospasm) and the intestine (producing abdominal pain).

■ Skin itching (produced by histamine in combination with kinins and prostaglandins).

■ Pain due to stimulation of nociceptors (see Chapter 19).

■ Increased antigen-presenting cell capacity, upregulation of Th1 cells and chemotaxis of eosinophils and neutrophils into affected tissues.”

Th1 and Th2 helper cells - balance is key to our energy level and allergy symptoms.

Th1 immune cell dominance may be better at fighting viral infections but make autoimmune issues more likely too - a body ready to fight. Food sensitivities, gut issues, and brain fog (unclear thinking ability) may also be more common with Th1/Th17 dominance over Th2 immune cells. Membrane problems can be causing more leaky bowel or blood brain barrier issues leading to food reactions or migraines. Supplements like echinacea or astralagus that promote Th1 cells would not be helpful. (19)

Th2 dominance isn’t good either. It may also increase food and seasonal allergies, constricted airways, eczema, histamine intolerance symptoms, and brain fog, but fighting extracellular infections like bacteria or parasites might be more effective. (20) Naringen from citrus peel or pulp is a flavonoid that opens airways and helps asthma patients in part because it promotes a reduction in Th2 immune cells and an increase in Th1, (26) (it also activates bitter taste receptors within the lungs which opens airways, thins mucus, and moves it up and out.)

Brain hyperexcitability and even seizures can be symptoms of low histamine as the H1 receptors modulate seizure activity, but histamine excess may also be a factor. (21) Many things are needed in a narrow range for optimal function.

Phytonutrients that are antagonists of NMDARs - may help reduce damage from overactivity.

There are many phytonutrients that may help reduce damage from excess activity of NMDARs by inhibiting the receptors. Curcumin (30) and ginseng are included in a review article about many types of receptors; also some Traditional Chinese Medicinals, and kaitocephalin, a newer discovery from a fungal extract. (11)

“On the other hand, NMDAR antagonism was observed with

• triterpene saponins (20(S)-protopanaxatriol (34, Fig. S1), ginsenoside 20(S)-Rh2 (35, Fig. S1) and ginsenoside 20(S)-Rg3 (36, Fig. S1)), [found in ginseng],

• phenylpropanoids (α- and β-asarone (37 and 38, Fig. S1) and eugenol (39, Fig. S1)), flavonoids (isoquiritigenin (49, Fig. S1)),

• curcuminoids (curcumin (50, Fig. S1)), [found in turmeric],

• mono (isoborneol (51, Fig. S1)) and diterpenes (15-methoxy-pinusolidic acid (41, Fig. S1)), alkaloids ((−)-huperzine A* (42, Fig. S1), ibogaine (11, Fig. S1), lophocladine A (46, Fig. S1), rhynchophylline* (52, Fig. S1), isorhynchophylline* (53, Fig. S1) and (−)-kaitocephalin (59, Fig. S1)), [*used in Traditional Chinese Medicine] [Ibogaine - may help opiate withdrawal and is being studied for alcoholism. 16] [Kaitocephalin, - antagonist of glutamate receptors, neuroprotective extract from a fungus. 13]

• peptides (conantokins (47–49, Fig. S1) and histogranin (57, Fig. S1)), [Conanotokins - derived from the venom of marine Conus snails, conotoxins specific to antagonism of the NMDARs. (14) ] [Histogranin - originally isolated from bovine adrenal medulla, now used for preventing NMDA induced convulsions. (15)]

• polypeptides and iridoids (8-O-E-p-methoxycinnamoylharpagide (55, Fig. S1) and harpagide (56, Fig. S1)), [harpagide - PubChem].

having pharmacological activity in the CNS, particularly in neurodegenerative diseases such as AD, where it is underlined an excessive activation of NMDARs [77]. Indeed, the referred compounds, acting by NDMARs antagonism, in general way, inhibit the excitotoxicity mediated by glutamate, thus decreasing the Ca2+ intracellular levels, promoting an attenuation of oxidative stress and, consequently, decreasing cells damage [4,78,79].” (11)

All of the nutrients are needed in balance and some additional chemicals often become essential as we age or during illness. How often we eat a food may also increase risk of becoming sensitized to it, in a way that may increase histamine and migraines or other symptoms the next day, but would not show a positive lab test for bee-sting or peanut butter type of food allergies.

Many factors can affect whether some, a little, or a lot, of a negative food will be as damaging to an individual, or whether a healthy food or phytonutrient may be inflammatory to you specifically as an individual. Curcumin is a TRP channel activator, which can be an irritant for colitis/IBS. It might help protect the brain, but it has to get there first, and it won’t if it just causes diarrhea - lost the curcumin, and a lot of beneficial electrolytes - a net negative.

Misfolded proteins may lead to more NMDAR activity.

Misfolded proteins cannot do their normal function. Prion proteins in their proper formation help down regulate NMDARs so misfolded ones would be allowing more over excitement of NMDARs when glutamate is present in excess. (8) Glutamate is heavily used in the food industry in various flavoring agents and seasonings. Processed foods can provide an excess.

“Recent preclinical research has demonstrated that the endogenous cellular prion protein (PrPC) protects against excitotoxicity by downregulating a subpopulation of NMDARs, suggesting that progressive misfolding of PrPC into the disease-associated form of the protein (PrPSc) may result in the loss of this neuroprotective function and subsequent neurodegeneration in Creutzfeldt-Jakob disease (9).” (8)

A review of small molecules that can help reduce Endoplasmic Reticulum stress from erroneous protein accumulation found the colorful delphinidin to be likely to be the most effective.

Delphinidin, protects against misfolded proteins.

Delphinidin is interesting because it is an acidity sensitive pigment, an anthocyanidin, which will change color based on the acidity level of the environment. In a more acidic pH it is a red color and in a more alkaline setting it is a brilliant blue, named for the Delphinium flower. The pigment is also found in Viola species. The viola F3′5′H gene is involved in plant production of delphinidin. (4) (*Experiments have been ongoing to try to develop a true blue rose. Normal roses do not make delphinidin.)

Delphinium, Photo by Yoksel 🌿 Zok on Unsplash

Delphinidin is found in berries, black beans and purple/black varieties of other produce and grains, and in the brilliant red pomegranate, goji berries and possibly in edible sumac along with myrtillin. Myrtillin is a 3-glucoside of delphinidin. The brilliant purple of eggplant is also a good source. (5, viewable at 6))

Food sources of delphinidin: Blue Lotus Flowers, Blue Butterfly Pea Flowers, Chicory (flowers probably), Black beans, black rice, purple varieties of cabbage, carrots, cauliflower, corn, & other produce, eggplant, pomegranate/peel, raspberries, goji and maqui berries, bilberries, blueberries. 

Delphinidin was found second most drug like candidate of a molecular docking study of phytonutrients that may be effective inhibitors of SARS-CoV-2. Articanin, found in Bay leaves (Laurus nobilis), was found to be the most drug like candidate from the top thirty phytonutrients that were identified. It is a sesquiterpene lactone, (7), similar to artemisinin, the anti-malarial extracted from Sweet Wormwood, (Artemesia annua). Quercetins and a hydrolysable tannin were also among the top thirty. (7) For more details, see: Phytonutrients, Molecular Docking List

Allosteric Modulators ~ 3D electrical field stabilizers.

Receptors and the chemicals that interact with them are a little like three-dimensional puzzle pieces that may fit together precisely with a strong binding energy, or more of almost fit with a weak binding energy. A third molecule nearby may interact in a way that is like a third puzzle piece that helps hold the first two in place. Flavonoids can act as allosteric modulators. Any of the zinc ionophores/iron chelating type of anti-microbials will have an electrical effect and be able to donate or accept electrons.

“Finally, they may also act as allosteric modulators, i.e. through their binding to the allosteric centre of the receptor and, consequently, change the receptor structure [28] – thus, affecting the interaction between the receptor and the primary ligand – or interfere with receptor expression (Fig. 2a and b). Indeed, studies addressing the effect of flavonoid supplementation in humans and animal diets have shown improvements in cognition function possibly by protecting vulnerable neurons, enhancing existing neuronal function, stimulating neuronal regeneration and counteracting the oxidative stress [29].” (Silva, et al, 2019) (11)

Delphinidin is also special because it contains not just one, or two, or three, but FOUR ions of magnesium! Really, that is exciting. Magnesium may be what adds the sparkle of health to our eyes - moisture. Each ion of magnesium can keep a cloud of up to 18 molecules of water within its stabilizing electrical field.

A symptom of magnesium deficiency that is not in the scientific literature - my own theory which needs research for support - may be dry eyes, lack of sparkle - a more glistening white to the whites of the eyes instead of a more opaque, flat white. Like Glossy paint for trim instead of the flat white for ceilings.

Delphinidin has been found helpful for the treatment of severe dry eyes. An extract of maqui berries has been found effective for “improving eye dryness and fatigue in humans”. (12)

Allosteric modulators are among the types of chemicals that can act as modulators of NMDAR activity.

“This class of chemical probes we show regulates both channel gating and ionic selectivity, and thus establish a new precedent in ion channel biology that could allow the tuning of specific facets of NMDAR signaling that contribute to circuit function or are dysregulated in disease. For example, biased allosteric modulators that enhance NMDAR open probability while decreasing NMDAR permeability to Ca2+ the enhancement of NMDAR currents while protecting neurons from calcium-induced toxicity.” (10)

If the third puzzle piece is affecting the opening of the ion channel of the NMDAR in a way that prevents calcium entry, then the damaging effects of excess NMDAR stimulation would be reduced.

Take home point - think about what you are eating - is there going to be helpful puzzle pieces in the mix? or damaging ones? Aim for more helpful ones in your menu planning, and fewer that may be damaging in general or to you individually.

Our unique genetics and life experience can increase or decrease risk of food sensitivities. Leaky bowel membranes and vitamin D adequacy are a big factor in risk of developing food allergy or autoimmune conditions that involve molecular mimicry. Methyl Bs help with detoxification of formaldehyde and breakdown of excess histamine. Magnesium and other trace minerals protect against oxidative stress damage and omega 3 fatty acids.

Summary points

If you want to protect your brain and body from misfolded proteins and neurodegenerative conditions:

• Do not overeat regularly, especially at night. Lower carbohydrate diet balance may be helpful, 30% calories from carbs, 20-25% protein, 45-50% from fat is the ratio I use.

• Have blackout curtains or an eye cover to promote melatonin production and healthy circadian cycle function.

• Drink plenty of water. Do full range stretching and aerobic exercise to promote lymphatic flow and detoxification.

• Avoid excess use of glutamate containing foods (tomatoes too, not just MSG).

• Avoid excessive alcohol use, and caution with monoamine oxidase inhibitors and acetaldehyde medications - “20% of Europeans” may be affected by their use of: “verapamil, clavulanic acid, chloroquine derivatives, acetylcysteine, amitriptyline, metamizole, and isoniazid.” (25)

• Have adequate inositol, B6, methyl folate, magnesium, copper, glycine - and other mitochondrial support nutrients and cofactors.

• Increase use of delphinidin containing foods or the flower teas. Dandelion leaf or root may also be helpful for reducing misfolded protein risks.

• Increase use of NMDAR antagonists/modulators such as curcumin, (30), ginseng, [and all those other odd names, 11].

SARS-CoV-2 chimeric spike protein has 7 prion like domains which aren’t broken down by plasmin.

With the chimeric spike protein, we have bigger problems. It has seven prion like domains, and it has been found that our immune cells break down the spike into those sections - maximizing practically the risk. The fibrous-like segments are amyloid - misfolded but unlike other amyloids in that they have arm and leg like extensions. Our normal plasmin method for breaking down amyloid does not work on the spike prion-like sections. They collect instead into fibrotic clots. (28, 29)

What to do? Everything else plus - try Serrapeptase and nattokinase (enzymes that break down fibrotic clots) taken three hours separate from meals and it may help the body keep up with break down and removal of the chimeric amyloids. I take it in the middle of the night or very early in the morning.

People may experience symptoms after a CoV infection, or from passive exposure to people who recently got a CoV mRNA injection, and people who received CoV injections would be at most risk because far more spike is produced, and throughout the body. The chimeric spike was modified for the injections and may be worse than the infection version.

Serrapeptase in particular may be helpful as it is a silkworm enzyme and silkworm fiber has been used in bio-nanotech design. (numerous search results available) With the number of known chimera sequences in the spike there is no reason to disbelieve that silkworm fiber may be involved too.

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.

Reference List

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