Endoplasmic Reticulum stress,

misfolded proteins, allosteric modulators

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

By Jennifer Depew, RD, June 7, 2022

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

Introduction:
This article combines the last two posts, looking closer at the link between histamine excess
which can be common in Alzheimer’s and is being seen in LongCovid. However, histamine
excess is often unrecognized and lab tests can be inconclusive or false negatives.

Histamine excess is part of inflammatory reactions caused by many factors of modern life
(NF-kB is part of the inflammatory pathways) and when the inflammation keeps escalating it
may increase risk for misfolded protein accumulation leading to cell death. This occurs in the
hippocampus in Alzheimer’s patients as NMDA receptor over activity is also involved and both
NMDA and H1 histamine receptors are more concentrated within the hippocampus. (H1-R, 2,
viewable 3) (NMDAR - 17, viewable at 18)

Anti-inflammatory Nrf2 pathways would be protective against cell death in the case of excess
misfolded proteins. (Subsection_Nrf2 function) Anything promoting NF-kB such as
degranulation of mast cells would also be inhibiting Nrf2 as the two proteins share a circadian
cycle protein. The histamine excess and increase in NMDA receptor activity can both affect
mood in a manic, anxious, or irritable way depending on the person’s mood.

Is delirium and histamine excess similar? A paper proposes that the idea needs more study and
more effective non-pharmaceutical solutions.

“Histamine is arguably the most pleotropic neurotransmitter in the human

brain, and this review provides a rationale, and proposes that this
neuroactive amine plays a role in modulating the characteristic features of
delirium.” (53)

“In general, the most commonly described neurochemical changes associated with
delirium include deficiencies in acetylcholine and/or melatonin, together with excess
in glutamate and monoamines dopamine and noradrenalin, and bi-directional
 activity alterations (e.g., decreased or increased activity, depending on delirium
presentation and trigger) in serotonin, γ-aminobutyric acid (GABA) and/or,
importantly, histamine (Maldonado, 2013).” (53)

“The unknown nature of etiology for most types of delirium and the complete lack of
placebo-controlled Randomized Controlled drug Trials, the lack of any
FDA-approved drug treatment for delirium and the wide ranging nature of drugs
with multiple chemical neurotransmitter pathways affected (variable across NHS
Trust hospitals) used to treat it is clearly a major problem. Furthermore the lack of
effective non-pharmacological approaches is also problematical (Wade et al., 2015,
2019; Richards-Belle et al., 2018) Without understanding more about the underlying
nature of the pathways involved how can we hope to effectively and rationally treat
it?” (53)

Delirium is probably not fun and can be dangerous to self or others. If the brain is in
over-allergic mode - histamine hyperexcitability - that would be worth knowing. Because then it
would be possible to do something to reduce the inflammatory signaling by avoiding allergens
that lead to mast cell degranulation which releases histamine and promotes NF-kB; avoiding
lifestyle inflammatory factors that promote NF-kB; and using histamine and NMDA receptor
antagonists or modulating herbs or medications. Antagonists for the H3 histamine receptor may
also be helpful. (53)

This article contains a potential mechanism of action for how histamine excess and NMDA
receptor overactivity may combine in damaging the hippocampus in Alzheimer’s dementia and
other neurocognitive conditions. It also includes lifestyle and diet strategies that might help stop
the escalating hyperinflammation of overactive mast cells, too much NF-kB and not enough
Nrf2.

● First post, related background info: Nrf2 & NF-kB: 2 proteins to know.
● Second post - looks like spaghetti - Endoplasmic Reticulum… it got too long. I can’t
update it. The current version of it is in document form and has the full Reference List:
Misfolded proteins, H1 and NMDA Receptors.
● See Table 1 for details about solutions for reducing the inflammation spiral, and Protocol
Collation and Therapy Goals for more info & references.

Graphical Abstract: Hyperinflammation - a positive feedback loop.

Hyperinflammation, a positive feedback loop. Stress leads to NF-kB which inhibits Nrf2,
which we need for cell and mitochondria maintenance.

Hyperinflammation, a positive feedback loop.

1. NF-kB causes Mast cells to release histamine and other inflammatory chemicals.
○ Solutions include promoting Nrf2, as activation of it will inhibit NF-kB.
○ Reduce stressors that promote NF-kB - infection or chimeric spike; modern life -
see Table 1.
○ Reduce histamine in the diet and avoid any allergic triggers. Increase methyl
folate and avoid formaldehyde too (also requires folate for breakdown.)
2. Histamine excess can cause leaky membranes and increased sensitivity to allergens or
autoimmune risks from food proteins that are similar to ours.
○ Solutions include avoiding histamine containing or triggering foods; increase
methyl folate and avoid unmethylated folic acid or cyanocobalamin in
supplements or fortified foods.
3. Histamine over activity at the H1 receptor could add to NMDAR over activity by not
allowing down regulation of the NMDA receptors by an unknown agonist of H1 histamine
receptors.
○ Until someone discovers the mystery agonist which might help as a
supplement/treatment, other phytonutrients that down regulate NMDAR or
modulate the entry of calcium may be protective against hippocampus damage
caused by NMDAR over activity.
 4. NMDAR activity can activate vitamin A or carotenoids to Retinoic Acid.
○ Excess dietary glutamate is a frequent cause of excessive NMDAR activity. The
solution is to avoid glutamate rich foods or seasonings.
5. Retinoic Acid causes Mast Cells to degranulate, releasing more histamine.
○ Epstein-Barr Virus is a known cause of a gene change in a liver enzyme that
activated vitamin A or carotenoids to Retinoic Acid. Vaccine injury is theorized to
also possibly be a cause of a similar change. For life then, too much mast cell
activation and histamine excess might be an underlying health factor. The
solution is to avoid foods or supplements rich in vitamin A and carotenoids, or
retinoic acid medications.
○ See document: Retinoid Toxicity.

More detail about the positive feedback loop is included after the discussion of Table 1 farther
along.

Table 1: Modern life - promoting NF-kB.

Is hyperinflammation a causal factor in Alzheimer’s dementia? Is the misfolded protein

accumulation a result of increased inflammatory white blood cell activity rather than the cause?
Allergy or autoimmune damage within the brain?
The amount of amyloid in the brain is not always consistent with more severe symptoms. So,
what is causing more severe Alzheimer’s symptoms or damage? Histamine hyperexcitability
itself can resemble schizophrenia or Alzheimer’s so may it be causal of schizophrenia or
Alzheimer’s?

Hyperinflammation may be a positive feedback loop and hyperexcitability of histamine excess is

a brain modulator out of control - positive feedback loop. Whatever thoughts or mood is present
can escalate whether fear, anger, or grandiose mania. Histamine excess may also prevent down
regulation of NMDARs by H1 histamine receptors that use a different agonist than histamine.
Leading to more NMDAR activity. Dietary glutamate is also a common cause of excess NMDAR
stimulation. Increased brain activity focused within the NMDAR rich hippocampus leads to
over-excitement of brain cells and can lead to their death in the region. The NMDAR activity can
stimulate more retinoic acid, which triggers mast cells, which degranulate and release
inflammatory cytokines and histamine, which leads to more histamine hyperexcitability.

Too much hyperexcitability and the brain damage may lead to symptoms of Alzheimer’s or may
present as schizophrenia-like before the more severe forgetfulness of dementia occurs.

Background Alzheimer’s dementia.

Alzheimer’s has been thought to be due to buildup of amyloid-beta misfolded protein tangles, or
problems with tau protein which helps stabilize microtubules - straight normally or arcing, not
tangled. Over 200 experimental drugs targeting the amyloid protein tangles have not helped
patient symptoms once reaching the clinical drug trial stage. Leaving the question - If the
amyloid tangles are correlated with Alzheimer’s but are not causal - then what is causal? What
is causing amyloid-beta to buildup and hippocampus damage to occur in the brains of patients
with Alzheimer’s dementia?

Background schizophrenia.

Schizophrenia is more of a set of symptoms that can have several nutrient deficiencies or
imbalance as a causal factor rather than ‘one’ condition with ‘one’ cause.

Toxoplasma gondii infection may be related to some cases. Low iodine/bromide excess,
hypothyroidism may be involved; low vitamin D and/or vitamin D receptor gene alleles; low
methyl folate and methyl B12, methylation gene alleles may be a factor; high dose niacin has
been found to be a very helpful treatment; and a zinc deficiency and/or excess of copper in
proportion to zinc may all be causal factors for worsening of schizophrenia-like symptoms. Lack
of zinc during prenatal development may increase the child’s later risk of schizophrenia. Lack of
the CBD equivalent with excess of the THC equivalent endocannabinoid due to a gene
difference, may also be an imbalance which CBD drops may help.

See post: The voices that people with schizophrenia are hearing may be their own. *High
powered microphones were used to record patients with schizophrenia and it was found that
they were hearing their own subvocal speech but not making the connection that it was their
own thoughts.
Personal story with schizophrenia like symptoms caused by histamine excess, low zinc, vitamin
D, and methyl B vitamins may have been additional factors:

Having had histamine hyperexcitability and having people tell me that I must have schizophrenia
based on my behavior during the histamine meltdowns, I can share that what it feels like is too
much, way too much going on. So many thoughts are flying through at such a fast rate that
remembering them doesn’t occur, let alone, possibly identifying their source (as yourself). It can
be a whirling, chaotic, scary, tornado of whatever shame or worry or fear that you might be
thinking.

Histamine excess can lead to self-injury or violence against others as the out-of-control thinking
is really irrational and quite difficult to control. I am glad to have survived it and discovered how
just changing my diet helped me avoid the mood meltdowns. If you have a choice to not to have
an out-of-control tornado in your mind, wouldn’t you take it?

I have a number of metabolic gene differences (post: BHMT and post: gene alleles) that
increase risk of methyl B deficiency, endocannabinoid, and likely zinc and B6. I had to modify a
number of daily habits, add zinc and B6 supplements, and avoid medical marijuana strains that
are very concentrated in THC but have no calming CBD or other non-euphoric cannabinoids.
Low vitamin D and hypothyroidism may also have been factors. Adding high dose niacin has
also helped. See post: Niacin & Early Treatment.

The diet changes are significant to avoid histamine, and would not be easy if a patient was
being provided standard US food or really almost any standard meal plans. Change needs to
occur with clinical research to show that the low histamine diet does help chronically ill patients
on average, and then the menu itself would be changed for the average special-needs facility.

Current medications are not very helpful and patients with schizophrenia were likely to have
better quality of life with the nutritional care strategies that were used a hundred years ago.

Putting a label on something and then saying the cause or cure are not known - but now you
have a label - may seem reassuring, but really it is a nocebo. You have a PROBLEM, and it is
not understood and cannot be helped. Or can it?

If we don’t try to find a solution, then a problem cannot be helped.

Hyperinflammation anywhere leads to fibrotic scarring and cell death eventually if left unchecked -
heart, liver, joints, nerves, all are at risk.

Hyperinflammation anywhere in the body can lead to fibrotic scarring and regions with dead
cells if the inflammatory signaling remains excessive over time. Increased numbers of white
blood cells were called to the area by inflammatory cytokines and proteins like NF-kB. Anything
that promotes NF-kB like stress or infection is also inhibiting Nrf2 because they share a
circadian cycle protein - both can’t actively use it at the same time for chemical reactions. NF-kB
would help fight an infection but lead to damage if chronically over active. Nrf2 is our DNA
repair, immune function, and promoter of glutathione production and other antioxidants that we
make for ourselves, and or our mitochondria.

What to do?

Change the modern lifestyle factors and remove individually inflammatory foods or other
stressors from life.

All of the factors in Table 1 are listed below with more detail. They all can increase NF-kB or
may lead to an increase - which also inhibits Nrf2. This puts us in a constantly inflamed state
without the normal circadian cycle of nightly maintenance by the Nrf2 pathways.

● Stress - physical exertion from overwork, or strenuous exercise; an immune challenge

from an infection or vaccination; or emotional stress - family or work issues, no
autonomy, financial stress or housing, fear, worry, loneliness, lack of purpose, repetitive
news messaging.
○ Stressors lead to oxidative stress and an increased need for B vitamins, vitamin
C, D, and magnesium and other trace minerals.
○ Niacin/nicotinic acid plus mitochondrial cofactors, other Bs and minerals, can
help promote NAD+ and protect against inflammation in a variety of ways.
● “Since then, numerous studies have reinforced the view that NAD+ levels are key to
neuronal function and survival. This includes the dependence on NMNAT2 and its NAD
synthesis activity for axonal survival (Yan et al., 2010). Supplementing may help protect
against Parkinson’s Disease and Alzheimer’s dementia and other neurologic conditions.
NAD-boosting regimens prevent and in some cases can reverse neuronal degeneration
associated with hearing loss, prion toxicity, retinal damage, traumatic brain injury (TBI),
and peripheral neuropathy (Brown et al., 2014; Dutca et al., 2014; Hamity et al., 2017;
Lin et al., 2016; Vaur et al., 2017; Yin et al., 2014; Zhou et al., 2015) ” (56)
○ Low nutrient levels can result quickly during acute or chronic stress.
Supplementing with nutrient rich foods or supplements can help reduce damage
caused by the oxidative stress and protect our mitochondria. Mitochondrial
dysfunction is frequently an early sign of problems in chronic degenerative
diseases. Promoting Nrf2 would help the body make more of our own
antioxidants, repair DNA damage, and increase immune function.
○ Low nutrient levels can then also increase mental illness symptoms - depression,
anxiety, paranoia and compulsive thinking, or irritability or rage. Mass Formation
Psychosis or group think might be more likely when also magnesium deficient.
● Circadian Cycle Disruption - Any light at night disrupts melatonin production and likely
other epigenetic changes that should be taking place in switching from daytime NF-kB
pathways (and others) to night time Nrf2 pathways (and others).
○ Black out darkness during sleep or an eye cover.
○ Avoid bright lights and screen time in the three hours prior to sleep or wear blue
light blocking glasses during those hours - may help insomnia.
○ Get full spectrum light or sunshine daily, in the morning ideally.
● Poor Sleep - causes reduced glymphatic flow in the brain which is needed to clean out
toxins.
○ Follow the Circadian Cycle sleep tips and consider magnesium adequacy. Epsom
salt soak (1-2 / week), 1/2 teaspoon of glycine or magnesium glycinate to provide
400 mg magnesium prior to bedtime may help.
○ Adequate zinc is needed for good sleep but may be taken at any time during the
day, and high doses may be better tolerated with a meal.
○ St. John’s Wort prior to bed may help if waking up around 4:00 am is a frequent
symptom. Waking in the early morning regularly may suggest low serotonin
levels.
○ Have a cool room for sleep with extra blankets to add or remove as needed. We
sleep better when our body is cooler, and our brain activity is slowed down. A gel
ice pack wrapped in cloth and placed on the forehead while trying to go to sleep
may help, similarly to how glycine can help with cooling the body down (it is a
brain calming amino acid).
● EMF - turn off devices at night, reduce exposure during the day, ideally.
● Poor Water intake and/or excessive diuretic beverages with inadequate non-diuretic
fluids. Leads to poor lymphatic and glymphatic drainage and risks from dehydration.
● Poor Exercise - full range body movement helps move fluid through the brain’s
glymphatic and body’s lymphatic systems.
● Over calories/carbohydrates and vegetable oils, and under nutrition - too little
quality protein and trace nutrients or phytonutrients.
○ Excess calories leads to poor autophagy - removal of cellular debris for reuse -
misfolded proteins included or a cell with an overloaded Endoplasmic Reticulum
that has been marked for apoptosis.
○ Excess carbohydrates leads to insulin resistance and inflamed fat cells that have
a difficult time accepting more fat.
○ Low protein would make it more difficult for the body to remove misfolded
proteins.
○ Excess omega 9 fatty acids in proportion to omega 3 leads to more Endoplasmic
Reticulum stress, enlargement and increased accumulation of misfolded proteins.
● Elevated Omega 6 to Omega 3 ratio - promotes NF-kB.
○ More people than realized may need fish, krill, or algal sources of EPA and DHA
omega 3 fatty acids as the average conversion rate from vegetarian sources like
walnuts and flax seed oil is not very good.
● Too much unmethylated Folic Acid and Cyanocobalamin in supplements and
fortified foods - may compete with methylated forms that are functional in a reaction.
Whether they are inflammatory may depend on the person. A clinical trial with CoV
patients found that B complex supplements and other nutrition support did help on
average - folic acid and cyanocobalamin were used. (1)
● Histamine in food - can cause a range of symptoms from seasonal allergies to
hyperexcitability.
● Increased sensitivity may occur for people with methylation gene differences as
folate is needed for breakdown of histamine.
 ● Increased sensitivity may occur if there is a genetic difference in the DOA
enzyme
● Loratadine and other H1 antihistamines can help, and possibly H2 or H3
histamine receptor antagonists also. (53)
● Flavonoids (60) such as quercetin, luteolin, and pomegranate catechins (61) may
help reduce mast cell degranulation. Pomegranate may also help regrow
hippocampal cells. (62)
○ Pomegranate prep, seeds and peel: G13. Pomegranate.
○ Also see this post about urolithin, a metabolite of pomegranate juice
formed by healthy microbes in our intestines and which can then cross
the blood brain barrier to reduce neuroinflammation in the brain:
Pomegranate, neuroinflammation, antimicrobial, metal chelator.
● Other beneficial phytonutrient rich foods: G10. Nrf2 Promoting Foods.

Regarding mast cells and pomegranate extract: “Pomegranate extract (POMx)

inhibits inflammation from activated human mast cells involved with connective
tissue destruction and proteolytic activity associated with cartilage destruction,
providing potential benefit for treating inflammatory diseases in which mast cells
play an active role (Zafar et al. 2009).” (61)

Regarding flavonoids: “The antihistaminic effect, histidine decarboxylase inhibition

and mast cell stabilising effect of flavonoids may play an important role in the anti
ulcer and anti secretory property of these compounds (Reimann et al, 1977;
Fewtrell & Gomperts, 1977; Ramaswamy et al, 1979).” (60)

● Excess dietary glutamate - or excess internal production - over activates NMDAR

receptors. Eventually mitochondrial dysfunction leads to use of glutamate and glucose
by fermentation which is less efficient but fewer nutrients and cofactors are needed.
Cancer cells have mitochondria that feed on glutamate for energy.
● Excess Vitamin A medications, foods, or carotenoid rich produce may be a
problem if over-activation to Retinoic Acid is occurring in the liver. This has been
seen to happen after an Epstein-Barr viral infection and may be a factor for some
vaccine injured (a theory developed prior to CoV injections). See: Retinoid Toxicity.
○ Low vitamin A is a more common risk for reduced immune function.
Reviewing the Retinoid Toxicity symptom list or my questionnaire may be helpful
as the effects can range throughout a variety of organ systems and also cause
skin or mood symptoms. Low level problems may remain undiagnosed as
anything specific or diagnoses for the various symptoms might be given - liver or
kidney disease being more end stage if the problem continues.
○ The solution if excess Retinoic Acid is a problem, is to stop using meds with
retinol (in many anti-aging skin products), and stop eating all rich sources of
vitamin A, retinal, and carotenoids. This is harder than it sounds as that includes
animal products and bright orange veggies and fruit (except citrus) and green
leafy vegetables. Reducing excess active vitamin A would reduce the
degranulation of mast cells by the Retinoic Acid. Less histamine would be
 released, and less histamine hyperexcitability or seasonal allergy symptoms
would be experienced.
● Glyphosate and organophosphates increase the risk of misfolded proteins.
Glyphosate may also have other effects on increasing hyperinflammation - positive
feedback loop of increasing inflammation without normal modulating actions reducing
some of the inflammatory activity. PFAS (67) and other modern toxins in foods and
medications such as bromide and fluoride also can cause problems. Low iodine in
comparison to the halides bromide, fluoride and perchlorates can lead to autoimmune
hypothyroidism or other low thyroid and endocrine symptoms.
● Other dietary substances that may cause inflammation in excess or for more sensitive
people - oxalates, lectins, TRP channel activators, or anything someone developed an
allergy or autoimmune sensitivity too.

Those are some of the things that we need to improve if we hope to reduce the inflammatory
effects of modern life, which can lead to misfolded proteins and neurodegenerative conditions.

Dietary influences and solutions:

Excess dietary glutamate and calcium can be risk factors for chronic degenerative conditions
and inflammation, 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, CoQ10, ALA, NAC or whey powder
for cysteine. Also, magnesium, manganese, copper, and other trace minerals in balance help
mitochondria and receptor and gene functions. Trace minerals may stabilize other chemicals, as
they tend to have an electrical charge as ions.

Solutions for misfolded proteins also include allosteric modulators to help stabilize or modulate
receptor function. Phytonutrient based solutions for histamine excess and/or NMDAR
antagonists can help reduce over activity. Liposomal curcumin would be a bioavailable form of
an NMDAR antagonist, and Vitamin D Receptor agonist with a reduced risk of hypercalcemia. It
also may help reduce misfolded protein risk by promoting Heat Shock Proteins (55) which tag
misfolded proteins for removal.

Lifestyle factors are important for reducing the promotion of inflammatory NF-kB and instead
promoting anti-inflammatory Nrf2 - 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.

See Table 1 for more details and Protocol Collation and Therapy Goals for other details and
references.
SARS-CoV-19 chimeric spike and the injection version cause
hyperinflammation.

SARS-CoV-19 infection or injections, or passive exposure to recently injected, may all also
cause a hyperinflammatory state. The injections, mRNA in particular, seem even more severe
as the mRNA sequence and chimeric spike were modified and is harder for the body to break
down. In order to “treat” CoV, we need to improve as much of the above list of modern life
problems that promote NF-kB — and also work on the special needs caused by inflammatory
chimeric spike effects. Hippocampal damage was seen in an animal based study of
SARS-CoV-2 S1 protein (S1 - subunit 1 of the chimeric spike, the part that can be free of the
base and may inhibit nAChR function).

"As mechanisms, we found that SARS-CoV-2 S1 protein exerted non-cell autonomous

hippocampal neuronal cell death by inducing interleukin-1 beta (IL-1β) expression from
glial cells." (64) *animal study, via (gab)

CoV injection adjuvants, Polyethylene glycol and graphene oxide, may have negative health
effects in addition to spike effects, and also increase inflammation or allergy-like reactions.

The fibrotic build up in CoV injected people who died suddenly reveal very unusual formations,
unlike any known fibrotic conditions.
https://www.naturalnews.com/2022-06-12-blood-clots-microscopy-suddenly-died.html

Believing that early treatment or preventive treatment can help - may also help it to help. The
stressors of fear and isolation alone can lead to symptoms of edema, congestion, pain and
fatigue - mimicking “Covid-19”. And the repetitive messaging of fear or risk, may increase the
chance of their occurring due to a nocebo effect. Think positive thoughts or listen to them and a
positive placebo healing effect may be more likely.

Severe Covid-19 is largely out of control inflammation due to excess promotion of NF-kB and
inflammatory cytokines by the chimeric spike. Increased NF-kB leads to reduced Nrf2 - which
we need to repair DNA and also to remove an overload of misfolded proteins safely.

Low Nrf2 would increase cell death from misloaded protein overload, Endoplasmic reticulum (ER)
stress.

Prion disease is generally deadly and fairly rapidly progressive. The misfolded prion can cause
normal ones to misfold also so the body would rather kill a cell that is overloaded with misfolded
proteins, safely by apoptosis (when Nrf2 is available), than let them collect and burst into the
extracellular fluid. (Subsection_Nrf2 function)

Endoplasmic reticulum stress can be due to a gene allele that produces a misfolded protein - in
Cov mRNA injected people, their cells are being told to make chimeric spike which contains
prion-like domains once broken down partially by white blood cells.
Genetic changes that cause a misfolded protein to be transcribed regularly can be a cause of
accumulation, seen in a patient with autism. (27) Misfolded protein accumulation begins in the
Endoplasmic Reticulum (ER), where proteins are made and identified as wrong only after they
are made. The problem occurs when too many problem proteins collect to be removed, the
overload leads to ER stress. When the ER is too overloaded, coupling with mitochondria leads
to apoptosis of the cell. (1) Low Nrf2 would make the death of the cell more likely. Misfolded
proteins can cause misfolding of other proteins leading to larger tangles outside of the cell.
Subsection: Endoplasmic Reticulum & misfolded proteins.

Mitochondrial dysfunction - fermentation of glutamate for energy.

Misfolded protein degenerative conditions* also seem to include mitochondrial dysfunction along
with histamine excess leading to or correlated with NMDAR receptor overactivity. Mitochondrial
dysfunction is also seen in cancer cells. Mitochondria are needed to cause the safe removal of
cells that are overloaded with misfolded proteins by apoptosis, so mitochondrial dysfunction
would leave a damaged cell adding misfolded protein to the surrounding tissue, increasing
misfolding exponentially within the region, or a dysfunctional senescent cell (37) might be the
result.

*Mitochondrial degenerative conditions may include Alzheimer’s dementia, Parkinson’s Disease,

ALS (Lou Gehrig’s Disease), and possibly Multiple Sclerosis (MS) in addition to prion diseases.
Some cancers also may lead to misfolded proteins. (1, 49) Misfolded proteins are also seen in
autism and can be genetic in nature - an allele is transcribing a misfolding protein instead of a
normal one. (27)

Mitochondria are needed to cause the safe removal of cells that are overloaded with misfolded
proteins by apoptosis, so mitochondrial dysfunction would leave a damaged cell adding
misfolded protein to the surrounding tissue, increasing misfolding exponentially within the
region, or a dysfunctional senescent cell (37) might be the result.

When hyperinflammation is allowed to escalate without check, then more and more cells are
damaged, or go into a senescent, not quite dead, but no longer functional, state.

Once the whole house is on fire, the flames may not be able to be extinguished. Earlier
provision of extra nutrients, protein, and immunomodulating phytonutrients can help put out tiny
fires while they are still tiny.

CoV chimeric spike and the injection adjuvants also can cause hyperinflammation and lead to
prion-like misfolding and fibrotic build up.

The damage from CoV infection involves hyperinflammation, however the injection version of
the chimeric spike is even worse for causing hyperinflammation and specific cell receptor
malfunction in addition to lodging in ACE2 receptors and disrupting their function. It also has
multiple prion-like domains which are exposed when our white blood cells break down the spike
into smaller pieces. (28, 29)
The chimeric spike protein is broken down into seven prion-like domains by our white blood
cells, and the prion-like sections seem resistant to our normal plasmin method for further
digestion and removal. (28, 29) The prion-like spike sections are leading to fibrotic build-up as
they can trigger other cellular proteins to misfold also, in a chain reaction, like a line of dominoes
falling once the first is knocked over.

Fibrosis/misfolded proteins, sHSPs, and our microtubules - axon support.

Fibrotic - fiber like, but a tangled plate of spaghetti instead of microtubules that are more like
straight, powerful antennae like scaffolding supporting our intra or extracellular fluid and guiding
chemicals and stabilizing our electrical fields. Microtubules also may support axons for our
nerves. Multiple sclerosis may have similar underlying issues as conditions more typically
thought of as misfolded protein conditions. (CoQ10, a mitochondrial cofactor is important for MS
care.)

Heat shock proteins are a stress response and are chaperone proteins that help prevent
misfolded protein tangles. (48) For a kitchen visual - raw egg is protein in a watery environment
- add heat and the water partially evaporates and the heat causes the proteins to change form -
denature - gentle heat leads to a softer texture, excess heat leads to a rubbery texture - the
proteins changed form and can not be uncooked. Chaperone proteins help stabilize and prevent
misfolding during the heat or other stress - the insulator sleeve around a cold drink in the
summer.

Adequate protein is necessary to have adequate chaperone proteins and other important
proteins such as PERK, AFT6, and GRP78 that help prevent misfolded proteins in the
Endoplasmic Reticulum. (Subsection_ER)

“Amino acid deprivation seems to limit the heat shock factor (HSF1) activity, which
plays an important role in the synthesis of HSPs. Cells cultured with either leucine,
lysine or glutamine deprivation show reduced HSF1, as well as HSPs mRNA levels.
Thus, it is suggested that amino acid deprivation can compromise the defense
capacity of the organism, since it may lead to the reduction of HSP synthesis [33].”
(47)

Certain phytonutrients or their food sources may help protect against misfolded proteins by
promoting Heat Shock Proteins.

“This chapter briefly describes recent findings in the effects of phytochemicals on

oxidative stress-involved ischemia/reperfusion injury, obesity, and liver diseases
through regulation of heat shock proteins. These phytochemicals include caffeic
acid phenethyl ester from bee glue, synthetic oleanane triterpenoid CDDO-Im,
curcumin from Indian spice turmeric, resveratrol from red grapes, naringin
found in grapefruit, epigallocatechin-3-gallate from green tea, anthocyanins
from pomegranate, and flavonoids.” (55)
Is prion disease airborne? CoV infection or passive exposure to injected people is airborne and
can spread in body fluids.

Airborne? Classic prion disease CJD or Mad Cow Disease were thought to only spread by
eating tissue with the misfolded prions or exposure directly to the prions, however exosome
spread might be a possible airborne risk. Airborne spread may be an even greater risk from
people who recently received CoV mRNA injections (the first two months post injection seems to
have the greatest risk for causing passive symptoms in others). Animal research was successful
at injecting one animal and having other non-injected animals in the same living area also
produce the desired antigen - it was called passive vaccination by way of exosomes containing
the injected genetic material being passed from the injected animals to the non-injected ones.
See: Exosomes.

More detail about the Hyperinflammation positive

feedback loop:
1. Degranulation of Mast Cells releases histamine and promotes NF-kB.

As we age many of our previous functions aren’t working as well. Inflammation can cause mast
cells to degranulate sending out histamine, cytokines and promoting NF-kB which leads to other
inflammatory signaling. Inflammation within our lymphatic vessels can lead to increased white
blood cells in the area which can increase fibrosis and cell damage in the area if it continues.
Lymphatic function might also be reduced leading to more buildup of toxins in extracellular
areas.

“We found that the reactivity of aged contracting lymphatic vessels to LPS-induced
acute inflammation was abolished and that activated mast cells trigger NF-κB
signaling in the mesentery through release of histamine. … We conclude that
proper functioning of the mast cell/histamine/NF-κB axis is necessary for reactions
of the lymphatic vessels to acute inflammatory stimuli as well as for interaction and
trafficking of immune cells near and within the collecting lymphatics.” (54)

*LPS - a bacterial endotoxin that CoV spike worsens the effects of.

2, 3, 4. H1-Rs & NMDARs; Hippocampus - center for daily memory formation, at risk from dietary
glutamate or histamine excess.

The hippocampus is an early target in Alzheimer’s because it has both more NMDA receptors
(NMDARs) than average and more H1 histamine receptors.

An agonist of NMDAR receptors, dietary glutamate, is common in modern life and it can be
made internally. Agonists are activators, too much activation of the NMDA receptor can lead to
an influx of too much calcium into the brain cell leading to excitement. The glutamate foods or
seasonings can lead to addictive overeating as they are stimulating to the brain - tasty and the
exciting feeling may promote ovr-eating. Too much overactivity of a cell can lead to cell death.
Subsection: Hippocampus has more NMDARs.

The hippocampus also has more H1 histamine receptors than average, so histamine excess
from degranulated mast cells, triggered by NF-kB inflammatory signaling, would also be leading
to inhibition of hippocampal cells. Histamine is a brain modulator in normal levels, helping us to
maintain an even midpoint between emotional extremes.

“In the cerebellum and hippocampus, abundant histamine H1 receptors are

localized in the dendrites of pyramidal and Purkinje cells (Hill et al., 1997).
Hippocampal activation of histamine H1 receptors induce the inhibition of firing and
hyperpolarization in hippocampal neurons (Haas, 1981).” (51, viewable 52)

The different types of histamine receptors have slightly different roles within the brain and body.

“Histamine driven H1 and H2 receptor-mediated actions are mostly excitatory, while

H3 receptors act as inhibitory auto- and heteroreceptors…” (53)

4. NMDARs; Prion misfolding can lead to increased NMDAR activity.

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.

3, 4. NMDAR and the H1 histamine receptor mystery modulator - down regulator.

NMDAR receptors are a 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! An unknown to
discover and name! 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
unknown 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. Subsection: Allosteric Modulators.

Curcumin is a Vitamin D receptor agonist that reduces risk of calcium excess in comparison to
taking vitamin D supplements. It may help reduce toxicity of amyloid and inhibit amyloid-beta
fibril formation, results have been inconclusive. [The Essential Medicinal Chemistry of Curcumin,
34 ] Curcumin is also an NMDAR antagonist. (11, subsection: Phytonutrients-NMDAR
antagonists). It is more bioavailable in liposomes, which may form in food preparations that
contain phospholipids in a watery broth or beverage (Golden Milk). See
Curcumin-bioavailability, within Phytonutrients, Molecular Docking - the synergy of soup - it may
be really good food!

5.Mast cells are also degranulated by Retinoic acid.

See Retinoid Toxicity. An excess may be activated by the liver in response to a viral infection
such as Epstein-Barr Virus and possibly traditional vaccination injury.

Disclaimer: This information is being provided for educational purposes within the guidelines of
Fair Use. It is not intended to provide individual health guidance.

Reference List

Full Reference List, linked within the subsections, is available in the document version:
Misfolded Proteins, H1 and NMDA Receptors.

Subsections

1. Inflammation triggers Mast cells increasing histamine and

NF-kB, which reduces Nrf2 and our ability to remove bad proteins.
Inflammation leads to fibrosis by way of excess Misfolded proteins in the Endoplasmic reticulum
(ER) which can lead to cell death. If the ER becomes too overloaded and no Nrf2 is available to
help then coupling with mitochondria leads to apoptosis of the cell. Mitochondrial dysfunction
could then leave damaged cells leaking misfolded proteins into the extracellular fluid
(speculation).

1.1 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 many 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)

1.2 Nrf2 function is needed to protect against death of cells due to ER

stress apoptotic signals.
Loss of Nrf2 function can lead to increased apoptosis of cells due to Endoplasmic Reticulum
stress. (36) Meaning that Nrf2 function likely is helping to protect cells when ER stress is
reaching overload. When misfolded or bad proteins are activating the PERK protein, it would
then activate Nrf2 in order to reduce the oxidative stress imbalance in the Endoplasmic
Reticulum. (37) A lack of Nrf2 therefore would be increasing the risk of neurodegenerative
conditions involving misfolded protein accumulation.

“The PERK kinase can also phosphorylate the NRF2 protein, which translocates into the
nucleus and activates the transcription of genes that maintain the redox homeostasis
(31);” (37)

Hyperinflammation or a CoV infection or injection/passive exposure may be increasing risk for

misfolded protein accumulation due to nutrient deficiency, hypoxia, increased oxidative stress,
and the effects of an infection. The increased production of spike protein might lead to an
excess of “nascent client” - initially formed proteins that are not folded properly yet (a full basket
of clean but unfolded laundry) and a lack of oligomerization partners or chaperone proteins.

“For several reasons including mutations, inadequate stoichiometric amounts of

oligomerization partners, shortage of chaperone availability, increase in nascent client
 proteins, nutrient deprivation, viral infection, hypoxia, and oxidative stress, unfolded or
misfolded proteins can accumulate in the ER lumen, aggregate, and hence become toxic
and detrimental to cell survival.” (37)

Viral infection can lead to a rapid expansion of ER membranes and capacity of the organelle to
hold more proteins. Elevated fatty acids also led to expanded ER capacity and it involved
silencing of PERK and activation of ATF6.

“This again involves ATF6α but not its classical UPR transduction pathway (67). ER
expansion involving the UPR can also occur in pathological conditions. ... Pathological
elevation of fatty acids induced ER expansion, which was reversed by blocking the
PERK branch via the chemical chaperone 4-phenyl-3-butenoic acid (4-PBA). (94)*”

*94=43-excess oleate - an omega 9 fatty acid. Too much intake of soy oil in chicken’s diet can
lead to reduced omega 3 EPA/DHA in the eggs, (44), while increasing omega 3 can help reduce
omega 9/oleate levels in humans. (45)

“Viral infection is also able to promote ER expansion through UPR-dependent and

-independent pathways (19, 93, 141).” (37)

1.3 Cell senescence - defective cell that becomes unremovable by normal apoptosis.
Cell senescence may occur when a cell becomes too enlarged and may be unresponsive to
normal mitotic (cell division) or apoptotic signaling (controlled cell death by white blood cells). It
may also be multinucleated which is a common risk with CoV infections as the SARS-CoV-2
virus promotes multinucleated syncytia.

“Senescence could be defined as a cellular state characterized by specific genetic,

epigenetic, metabolic, and morphological alterations culminating in an irreversible
cell-cycle arrest. These changes rely on profound modifications of their transcriptome,
proteome, and secretome (6, 7, 28, 112). The overall morphology of the cell is altered at
senescence, with an increase in cell size and a change in cell shape. Nuclei and nucleoli
are often bigger than in proliferating cells, and senescent cells are frequently
polynucleated (30, 143).” (37)

“The characterization of the senescent-associated secretory phenotype (SASP) showed

an enrichment in proinflammatory cytokines, growth factors, extracellular matrix
components, and remodeling enzymes of the extracellular matrix (28).” (37)

1.4 Misfolded proteins are involved in Alzheimer’s, Parkinson’s, prion

disease, some cancer and autism. It is also a risk with CoV.
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 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].” (49)

1.5 Calorie excess, undernutrition, a lack of protein, nutrients, essential

omega 3’s and phytonutrients.
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.

2. NF-kB and H1 Receptors.

The symptoms of seasonal allergies linked to histamine excess and H1 histamine receptor
activity are inflammatory - linked to inflammatory proteins and cytokines released by mast cells
along with histamine. The histamine H1 receptor affects inflammatory NF-kB and others that it
leads to and H1 antagonists may help. (32)

Some antihistamines act on the H1 receptor but not all equally, others are antagonists for the H2
or H3 histamine receptors. H1 receptor specific antagonists were needed to down regulate the
histamine induced NF-kB and AP-1 inflammatory effects. (32)

“Induction of AP-1 and NF-kappaB activities by histamine and the down-regulatory effect
of antihistamines required overexpression of the H1-receptor.” (32)

Note the reactivity was seen in animals with an excess number, an overexpression of
H1-receptors. While TNF-alpha effects were not reduced by the H1 antagonists. (32)

Loratidine, an antihistamine, helped reduce inflammatory protein levels by binding with proteins
on the NF-kB pathway. (31) Loratidine is a potent H1 receptor antagonist, commonly used for
treatment of seasonal allergy. (33)
 “The second generation H1-antihistamines such as fexofenadine (Allegra), loratidine
(Claritin), cetirizine (Zyrtec) have less of a sedating effect”...than… “first generation
H1-antihistamines such as diphenhydramine (Benadryl) and hydroxyzine (Vistaril/Atarax)
causes more side effects such as drowsiness.” - aocd.org/antihistamines.

Histamine receptors of all four types are prevalent in many areas of the brain and seem to be a
primary modulator of our alertness versus sleepiness. Caution with the first generation
antihistamines when CoV is also an issue as they may add to an anticholinergic effect.

“First generation H1 anti-histamines significantly increased daytime sleepiness and

nocturnal sleep quality. Some, including cetirizine and hydroxyzine, seemed to also have
negative influences on mood states. Outpatients who received cetirizine and hydroxyzine
treatments reported higher scores on the depression, anxiety, and fatigue sub-scales
compared to those who received desloratadine, levocetirizine, and rupatadine (Clegg
and Young, 2011). The sedating antihistamines are non-specific in their actions and
often have marked anticholinergic effects. Features of overdose include tachycardia,
blood pressure disturbances, dry mouth, ataxia, psychosis, convulsion and, notably,
agitation (Clegg and Young, 2011).” (53)

Chimeric spike, or hyperinflammation for any reason, also increases NF-kB which would inhibit
Nrf2. Solution: Nrf2 promoting foods and phytonutrients are also NF-kB inhibiting. Quercetin,
sulforaphane, resveratrol, curcumin, EPA/DHA, and many others.

2.1 Symptoms caused by H1 receptor activity.

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.”

2.2 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) Flavonoids like Naringen from
citrus peel or pulp may help. It 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.

3. H1 Receptor down regulation of NMDARs, and Histamine

Excess.
Coincidentally, histamine excess can also cause hyperexcitability that may cause symptoms that
could seem like schizophrenia. Chronic histamine excess may lead to a schizophrenia diagnosis
eventually and later Alzheimer’s dementia may be the diagnosis. The histamine excess also
targets NMDARs in the hippocampus - coincidentally - or causally?

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)

4. Hippocampus has more NMDARs and H1 receptors 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 H1 histamine receptors and extra
NMDAR receptors, (17, viewable at 18), than average. NMDAR receptors 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)

4.1 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. Liposomal curcumin may
be a bioavailable solution.

4.2 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. See
subsection: Delphinidin.

5. Retinoic acid activates mast cells and induces epithelial cell

differentiation, which may increase EBV infectivity.
“Abstract: Lytic Epstein-Barr virus (EBV) replication occurs in differentiated, but not
undifferentiated, epithelial cells. Retinoic acid (RA) induces epithelial cell differentiation.
The conversion of retinol into its active form, retinoic acid, requires retinol
dehydrogenase enzymes. Here we show that AGS gastric carcinoma cells containing the
lytic form of EBV infection have enhanced expression of a gene (DHRS9) encoding an
enzyme that mediates conversion of retinol into RA. DHRS9 expression is also
increased following induction of lytic viral infection in EBV-positive Burkitt lymphoma
cells. We demonstrate that the EBV immediate-early protein, BZLF1, activates the
DHRS9 promoter through a direct DNA binding mechanism. Furthermore, BZLF1
expression in AGS cells is sufficient to activate DHRS9 gene expression and increases
the ability of retinol to induce the RA-responsive gene, CYP26A1.” (57)

CYP26A1 - code for the enzyme and gene that transcribes it. It is an endoplasmic reticulum
protein that regulates the level of retinoic acid. In the case of the EBV more is being induced.

“Summary
This gene encodes a member of the cytochrome P450 superfamily of
enzymes. The cytochrome P450 proteins are monooxygenases which
catalyze many reactions involved in drug metabolism and synthesis of
cholesterol, steroids and other lipids. This endoplasmic reticulum protein acts
on retinoids, including all-trans-retinoic acid (RA), with both 4-hydroxylation
and 18-hydroxylation activities. This enzyme regulates the cellular level of
retinoic acid which is involved in regulation of gene expression in both
embryonic and adult tissues. Two alternatively spliced transcript variants of
 this gene, which encode the distinct isoforms, have been reported. [provided
by RefSeq, Jul 2008]

Expression
Restricted expression toward liver (RPKM 15.5) See more (58)
*also a small amount is expressed in the brain and placenta.

Solutions - magnesium, water, moderate calorie intake, good

sleep!

Also see subsection: What to do? and do the opposite of Table 1’s
NF-kB promoters.

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.

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].”

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

1. Guzel E, Arlier S, Guzeloglu-Kayisli O, Tabak MS, Ekiz T, Semerci N, Larsen K, Schatz

F, Lockwood CJ, Kayisli UA. Endoplasmic Reticulum Stress and Homeostasis in
Reproductive Physiology and Pathology. Int J Mol Sci. 2017 Apr 8;18(4):792. doi:
10.3390/ijms18040792. PMID: 28397763; PMCID: PMC5412376.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412376/
2. Gregersen N, Bross P, Vang S, Christensen JH. Protein misfolding and human disease.
Annu Rev Genomics Hum Genet. 2006;7:103-24. doi:
10.1146/annurev.genom.7.080505.115737. PMID: 16722804.
https://pubmed.ncbi.nlm.nih.gov/16722804/
3. da Silva DC, Valentão P, Andrade PB, Pereira DM. A pipeline for natural small molecule
inhibitors of endoplasmic reticulum stress. bioRxiv; 2022. DOI:
10.1101/2022.02.20.481203. https://europepmc.org/article/ppr/ppr456770
4. Katsumoto Y, Fukuchi-Mizutani M, Fukui Y, et al., Engineering of the Rose Flavonoid
Biosynthetic Pathway Successfully Generated Blue-Hued Flowers Accumulating
Delphinidin, Plant and Cell Physiology, Volume 48, Issue 11, November 2007, Pages
1589–1600, https://doi.org/10.1093/pcp/pcm131
https://academic.oup.com/pcp/article/48/11/1589/1910852
5. *Charu Lata Mahanta, Dipankar Kalita, Chapter 16 - Eggplant,
Editor(s): Amit K. Jaiswal, Nutritional Composition and Antioxidant Properties of Fruits
and Vegetables, Academic Press, 2020, Pages 273-287, ISBN 9780128127803,
https://doi.org/10.1016/B978-0-12-812780-3.00016-7.
https://www.sciencedirect.com/science/article/pii/B9780128127803000167
6. *Excerpt viewable at: Myrtillin - an overview, ScienceDirect.com,
https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/myrtillin
7. Al-Shuhaib MB, & Hashim H, Al-Shuhaib J, & Obayes D. (2022). Artecanin of Laurus
nobilis is a novel inhibitor of SARS-CoV-2 main protease with highly desirable
druglikeness. J Biomolecular Structure and Dynamics. 1-13.
10.1080/07391102.2022.2030801.
https://www.researchgate.net/publication/358038162_Artecanin_of_Laurus_nobilis_is_a
_novel_inhibitor_of_SARS-CoV-2_main_protease_with_highly_desirable_druglikeness
8. Kalia LV, Kalia SK, Salter MW. NMDA receptors in clinical neurology: excitatory times
ahead. Lancet Neurol. 2008;7(8):742-755. doi:10.1016/S1474-4422(08)70165-0
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589564/
9. N. Josset, J-M. Arrang, V. Armand, The Constitutive Activity of the Histamine H1
Receptor Interaction with the NMDA Receptor: Consequences in Epilepsy.
bioRxiv, 2021.11.02.466417; doi: https://doi.org/10.1101/2021.11.02.466417
This article is a preprint and has not been certified by peer review.
https://www.biorxiv.org/content/10.1101/2021.11.02.466417v1.full
10. Perszyk RE, Swanger SA, Chris Shelley C, et al., Biased modulators of NMDA receptors
control channel opening and ion selectivity. Nat Chem Biol. 2020 February;16(2):
188–196. doi:10.1038/s41589-019-0449-5
https://open.library.emory.edu/publications/emory:vqc40/pdf
11. Ana R. Silva, Clara Grosso, Cristina Delerue-Matos, João M. Rocha, Comprehensive
review on the interaction between natural compounds and brain receptors: Benefits and
toxicity, European Journal of Medicinal Chemistry, Volume 174, 2019, Pages 87-115,
ISSN 0223-5234, https://doi.org/10.1016/j.ejmech.2019.04.028.
https://www.sciencedirect.com/science/article/pii/S0223523419303344
1. **tangent, this is a very comprehensive review - this is one of twelve tables of
phytonutrients that interact with different types of receptors. “Table 12. Natural
products that interact with ApoE or LDL receptors. Structures of the compounds
in Fig. S1.” EPA, DHA, vitamin E, quercetin, curcumin, and a citrus fruit flavanoid:
5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone.
12. Yamashita SI, Suzuki N, Yamamoto K, Iio SI, Yamada T. Effects of MaquiBright® on
improving eye dryness and fatigue in humans: A randomized, double-blind,
placebo-controlled trial. J Tradit Complement Med. 2018 Nov 22;9(3):172-178. doi:
10.1016/j.jtcme.2018.11.001. PMID: 31193920; PMCID: PMC6544612.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544612/
13. Limon A, Reyes-Ruiz JM, Vaswani RG, Chamberlin AR, Miledi R. Kaitocephalin
antagonism of glutamate receptors expressed in Xenopus oocytes. ACS Chem
Neurosci. 2010 Mar 17;1(3):175-181. doi: 10.1021/cn900037c. PMID: 20436943;
PMCID: PMC2860192. https://pubmed.ncbi.nlm.nih.gov/20436943/
14. Conantokins - an overview, ScienceDirect.com,
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/cona
ntokins
15. Histogranin, pr.vwr.com, https://pr.vwr.com/store/product/10388863/histogranin
*unaffiliated
16. Shea Prueger, Ibogaine Research Review, Clinical Trials Explained, psychable.com,
https://psychable.com/ibogaine/ibogaine-research-review-clinical-trials-explained/
*unaffiliated
17. Sharma HS, 13 - Histamine Influences the Blood-Spinal Cord and Brain Barriers
Following Injuries to the Central Nervous System, Editor(s): Hari Shanker Sharma, Jan
Westman, Blood-Spinal Cord and Brain Barriers in Health and Disease, Academic
Press, 2004, Pages 159-189, ISBN 9780126390117,
https://doi.org/10.1016/B978-012639011-7/50017-6.
https://www.sciencedirect.com/science/article/pii/B9780126390117500176
1. “A higher density of histamine H1 receptors is found in the neocortex,
hippocampus, nucleus accumbens, thalamus, and posterior hypothalamus
(Schwartz et al., 1991). Lower densities of the histamine H1 receptors are
present in the cerebellum and basal ganglia (Villemagne et al., 1991; Hill et al.,
1997).” (17, viewable at 18)
18. Histamine H1 Receptor: an overview. ScienceDirect.com,
https://www.sciencedirect.com/topics/medicine-and-dentistry/histamine-h1-receptor
19. Joe Cohen, Th1/Th2/Th17 Dominance, Food Sensitivities & Gut Health. selfhack.com,
https://selfhack.com/blog/th1-th2-th17-dominance/
20. Medically reviewed by Nattha Wannissorn, PhD; Written by Puya Yazdi, MD, Are You
Th1 or Th2 Dominant? Effects + Immune Response. selfhack.com,
https://selfhacked.com/blog/supplements-foods-exercise-right-type-th1-vs-th2-dominanc
e/#:~:text=Th1%20dominance%20is%20evidenced%20by%3A%20Delayed%20food%2
0sensitivities%3A,This%20is%20also%20a%20symptom%20of%20Th2%20dominance.
21. Scherkl R, Hashem A, Frey HH. Histamine in brain--its role in regulation of seizure
susceptibility. Epilepsy Res. 1991 Nov-Dec;10(2-3):111-8. doi:
10.1016/0920-1211(91)90003-x. PMID: 1817952.
https://pubmed.ncbi.nlm.nih.gov/1817952/
22. Masuoka T, Ikeda R, Konishi S. Persistent activation of histamine H1 receptors in the
hippocampal CA1 region enhances NMDA receptor-mediated synaptic excitation and
long-term potentiation in astrocyte- and D-serine-dependent manner.
 Neuropharmacology. 2019 Jun;151:64-73. doi: 10.1016/j.neuropharm.2019.03.036.
Epub 2019 Mar 31. PMID: 30943384. https://pubmed.ncbi.nlm.nih.gov/30943384/
23. Panula P. Histamine receptors, agonists, and antagonists in health and disease. Handb
Clin Neurol. 2021;180:377-387. doi: 10.1016/B978-0-12-820107-7.00023-9. PMID:
34225942. https://pubmed.ncbi.nlm.nih.gov/34225942/
24. Mlcek J, Jurikova T, Skrovankova S, Sochor J. Quercetin and Its Anti-Allergic Immune
Response. Molecules. 2016 May 12;21(5):623. doi: 10.3390/molecules21050623. PMID:
27187333; PMCID: PMC6273625. https://pubmed.ncbi.nlm.nih.gov/27187333/
25. Shulpekova YO, Nechaev VM, Popova IR, et al. Food Intolerance: The Role of
Histamine. Nutrients. 2021;13(9):3207. Published 2021 Sep 15.
doi:10.3390/nu13093207 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469513/
26. Guihua X, Shuyin L, Jinliang G, Wang S. Naringin Protects Ovalbumin-Induced Airway
Inflammation in a Mouse Model of Asthma. Inflammation. 2016 Apr;39(2):891-9. doi:
10.1007/s10753-016-0321-7. PMID: 26920847.
https://pubmed.ncbi.nlm.nih.gov/26920847/
27. Ulbrich, Lisa et al. Autism-associated R451C mutation in neuroligin3 leads to activation
of the unfolded protein response in a PC12 Tet-On inducible system. The Biochemical
journal vol. 473,4 (2016): 423-34. doi:10.1042/BJ20150274
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747159/
28. Karin Söderlund Leifler, Possible discovery of mechanism behind mysterious COVID-19
symptoms. Linköping University, Medicalexpress.com,
https://medicalxpress.com/news/2022-05-discovery-mechanism-mysterious-covid-sympt
oms.html
29. Sofie Nyström et al, Amyloidogenesis of SARS-CoV-2 Spike Protein, Journal of the
American Chemical Society (2022). DOI: 10.1021/jacs.2c03925
https://pubs.acs.org/doi/10.1021/jacs.2c03925
30. Riza YM, Parves MR, Tithi FA, Alam S. Quantum chemical calculation and binding
modes of H1R; a combined study of molecular docking and DFT for suggesting
therapeutically potent H1R antagonist. In Silico Pharmacol. 2019 Feb 25;7(1):1. doi:
10.1007/s40203-019-0050-3. PMID: 30863716; PMCID: PMC6389732.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389732/
31. Triseptya Hunto S, Han Gyung Kim, Kwang-Soo Baek,et al., Loratadine, an
antihistamine drug, exhibits anti-inflammatory activity through suppression of the NF-kB
pathway, Biochemical Pharmacology, 177;2020, 113949, ISSN 0006-2952,
https://doi.org/10.1016/j.bcp.2020.113949.
https://www.sciencedirect.com/science/article/pii/S0006295220301775
32. Roumestan C, Henriquet C, Gougat C, Michel A, Bichon F, Portet K, Jaffuel D, Mathieu
M. Histamine H1-receptor antagonists inhibit nuclear factor-kappaB and activator
protein-1 activities via H1-receptor-dependent and -independent mechanisms. Clin Exp
Allergy. 2008 Jun;38(6):947-56. doi: 10.1111/j.1365-2222.2008.02990.x. PMID:
18498541. https://pubmed.ncbi.nlm.nih.gov/18498541/
33. Miadonna A, Milazzo N, Lorini M, Marchesi E, Tedeschi A. Inhibitory effect of the H1
antagonist loratadine on histamine release from human basophils. Int Arch Allergy
 Immunol. 1994 Sep;105(1):12-7. doi: 10.1159/000236797. PMID: 7522069.
https://pubmed.ncbi.nlm.nih.gov/7522069/
34. Nelson KM, Dahlin JL, Bisson J, et al., The Essential Medicinal Chemistry of Curcumin;
Miniperspective, Med Chem. 2017, 60, 5, 1620–1637, January 11, 2017
https://doi.org/10.1021/acs.jmedchem.6b00975
https://pubs.acs.org/doi/10.1021/acs.jmedchem.6b00975
35. Retinoic acid reference - Rachel D. Groth, Richard W. Tsien. A Role for Retinoic Acid in
Homeostatic Plasticity. Neuron, Vol 60;2, P192-194, OCT 23, 2008, Open Archive
DOI:https://doi.org/10.1016/j.neuron.2008.10.003 -
https://www.cell.com/fulltext/S0896-6273(08)00846-5 NMDARs increase retinoic acid.
36. Guozhu Sun, Zongmao Zhao, Jiadong Lang, Boyu Sun, Qitao Zhao, Nrf2 loss of function
exacerbates endoplasmic reticulum stress-induced apoptosis in TBI mice. Neuroscience Letters,
770;2022, 136400, ISSN 0304-3940, https://doi.org/10.1016/j.neulet.2021.136400.
https://www.sciencedirect.com/science/article/abs/pii/S0304394021007795
37. Olivier Pluquet, Albin Pourtier, and Corinne Abbadie, The unfolded protein response and cellular
senescence. A Review in the Theme: Cellular Mechanisms of Endoplasmic Reticulum Stress
Signaling in Health and Disease. American J Physiology-Cell Physiology 2015 308:6, C415-C425
https://journals.physiology.org/doi/full/10.1152/ajpcell.00334.2014
38. Guozhu Sun, Zongmao Zhao, Jiadong Lang, Boyu Sun, Qitao Zhao, Nrf2 loss of function
exacerbates endoplasmic reticulum stress-induced apoptosis in TBI mice. Neuroscience Letters,
770;2022, 136400, ISSN 0304-3940, https://doi.org/10.1016/j.neulet.2021.136400.
https://www.sciencedirect.com/science/article/pii/S0304394021007795
39. Sedeyn JC, Wu H, Hobbs RD, Levin EC, Nagele RG, Venkataraman V. Histamine Induces
Alzheimer's Disease-Like Blood Brain Barrier Breach and Local Cellular Responses in Mouse
Brain Organotypic Cultures. Biomed Res Int. 2015;2015:937148. doi: 10.1155/2015/937148.
Epub 2015 Nov 30. PMID: 26697497; PMCID: PMC4677161.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677161/
40. Nizamutdinova IT, Dusio GF, Gasheva OY, Skoog H, Tobin R, Peddaboina C, Meininger
CJ, Zawieja DC, Newell-Rogers MK, Gashev AA. Mast cells and histamine are triggering
the NF-κB-mediated reactions of adult and aged perilymphatic mesenteric tissues to
acute inflammation. Aging (Albany NY). 2016 Nov 21;8(11):3065-3090. doi:
10.18632/aging.101113. PMID: 27875806; PMCID: PMC5191886.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191886/ “We found that the reactivity of
aged contracting lymphatic vessels to LPS-induced acute inflammation was abolished and that
activated mast cells trigger NF-κB signaling in the mesentery through release of histamine. … We
conclude that proper functioning of the mast cell/histamine/NF-κB axis is necessary for reactions
of the lymphatic vessels to acute inflammatory stimuli as well as for interaction and trafficking of
immune cells near and within the collecting lymphatics.” (40)
41. Lee M, Lee NY, Chung KS, Cheon SY, Lee KT, An HJ. Roxatidine attenuates mast cell-mediated
allergic inflammation via inhibition of NF-κB and p38 MAPK activation. Sci Rep. 2017 Jan
31;7:41721. doi: 10.1038/srep41721. PMID: 28139747; PMCID: PMC5282503.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282503/ *H2 antagonist helped reduce NF-kB.
42. Carlisle, Casey & Prill, Kendal & Pilgrim, David. (2017). Chaperones and the Proteasome
System: Regulating the Construction and Demolition of Striated Muscle. Int J Molecular Sciences.
19. 32. 10.3390/ijms19010032. Carlisle, Casey & Prill, Kendal & Pilgrim, David. (2017).
Chaperones and the Proteasome System: Regulating the Construction and Demolition of Striated
Muscle. International Journal of Molecular Sciences. 19. 32. 10.3390/ijms19010032.
https://www.researchgate.net/publication/322017021_Chaperones_and_the_Proteasome_Syste
 m_Regulating_the_Construction_and_Demolition_of_Striated_Muscle Figure 2. The folding of
nascent client proteins by their chaperone and co-chaperones.
https://www.researchgate.net/figure/The-folding-of-nascent-client-proteins-by-their-chaperone-an
d-co-chaperones-Exemplifying_fig2_322017021
43. Peng G, Li L, Liu Y, Pu J, Zhang S, Yu J, Zhao J, Liu P. Oleate blocks palmitate-induced abnormal
lipid distribution, endoplasmic reticulum expansion and stress, and insulin resistance in skeletal
muscle. Endocrinology 152: 2206–2218, 2011. https://pubmed.ncbi.nlm.nih.gov/21505048/
44. Caroline MacDonald, Too much of a good thing? Heart-healthy oleic acid cuts omega-3 in eggs.
April 12, 2018, fooddive.com,
https://www.fooddive.com/news/too-much-of-a-good-thing-heart-healthy-oleic-acid-cuts-omega-3-
in-eggs/521220/
45. Su Mi Lee, Mi Hwa Lee, Young Ki Son, Seong Eun Kim, Yongsoon Park, Seo Hee Rha & Won
Suk An (2019) Omega-3 fatty acid decreases oleic acid by decreasing SCD-1 expression in the
liver and kidney of a cyclosporine-induced nephropathy rat model, Renal Failure, 41:1, 211-219,
DOI: 10.1080/0886022X.2019.1591996
https://www.tandfonline.com/doi/full/10.1080/0886022X.2019.1591996
46. Holzbaur EL, Scherer SS. Microtubules, axonal transport, and neuropathy. N Engl J Med. 2011
Dec 15;365(24):2330-2. doi: 10.1056/NEJMcibr1112481. PMID: 22168648; PMCID:
PMC3776444. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776444
47. Moura CS, Lollo PCB, Morato PN, Amaya-Farfan J. Dietary Nutrients and Bioactive Substances
Modulate Heat Shock Protein (HSP) Expression: A Review. Nutrients. 2018 May 28;10(6):683.
doi: 10.3390/nu10060683. PMID: 29843396; PMCID: PMC6024325.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024325/
48. Heat Shock Protein, ScienceDirect.com,
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/heat-shock-pr
otein
49. Penke, Botond & Bogár, Ferenc & Fülöp, Livia. (2015). Protein Folding and Misfolding,
Endoplasmic Reticulum Stress in Neurodegenerative Diseases: in Trace of Novel Drug Targets.
Current protein & peptide science. 17. 10.2174/1389203716666151102104653.
https://www.researchgate.net/publication/283456401_Protein_Folding_and_Misfolding_Endoplas
mic_Reticulum_Stress_in_Neurodegenerative_Diseases_in_Trace_of_Novel_Drug_Targets
50. Leal-Martínez F, Abarca-Bernal L, García-Pérez A, González-Tolosa D, Cruz-Cázares G,
Montell-García M, Ibarra A. Effect of a Nutritional Support System to Increase Survival
and Reduce Mortality in Patients with COVID-19 in Stage III and Comorbidities: A
Blinded Randomized Controlled Clinical Trial. Int J Environ Res Public Health. 2022 Jan
21;19(3):1172. doi: 10.3390/ijerph19031172. PMID: 35162195; PMCID: PMC8835093.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835093/
51. Blood-Spinal Cord and Brain Barriers in Health and Disease. Editor: Hari Shanker
Sharma, Academic Press, 2004, eBook ISBN: 9780080528229
https://www.sciencedirect.com/book/9780126390117/blood-spinal-cord-and-brain-barrier
s-in-health-and-disease
52. Histamine H1-Receptor, ScienceDirect.com,
https://www.sciencedirect.com/topics/neuroscience/histamine-h1-receptor
53. Chazot Paul L., Johnston Laura, Mcauley Edel, Bonner Stephen. Histamine and
Delirium: Current Opinion. Frontiers in Pharmacology, 10;2019,
DOI=10.3389/fphar.2019.00299, ISSN=1663-9812
https://www.frontiersin.org/article/10.3389/fphar.2019.00299
54. Nizamutdinova IT, Dusio GF, Gasheva OY, Skoog H, Tobin R, Peddaboina C, Meininger
CJ, Zawieja DC, Newell-Rogers MK, Gashev AA. Mast cells and histamine are triggering
the NF-κB-mediated reactions of adult and aged perilymphatic mesenteric tissues to
acute inflammation. Aging (Albany NY). 2016 Nov 21;8(11):3065-3090. doi:
10.18632/aging.101113. PMID: 27875806; PMCID: PMC5191886.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191886/
55. Wang, Xinyu & Rayalam, Srujana & Bhave, Vishakha. (2016). Heat Shock Proteins and
Phytochemicals: Role in Human Health and Disease. 10.1007/978-3-319-46340-7_11.
From the book: Heat Shock Proteins and Plants (pp.211-232)
https://www.researchgate.net/publication/310810278_Heat_Shock_Proteins_and_Phyto
chemicals_Role_in_Human_Health_and_Disease
56. Luis Rajman, Karolina Chwalek, and David A. Sinclair. Therapeutic Potential of
NAD-Boosting Molecules: The In Vivo Evidence. Cell Metabolism, 27;3, pp529-547,
March 06, 2018 https://doi.org/10.1016/j.cmet.2018.02.011
https://www.cell.com/cell-metabolism/pdf/S1550-4131(18)30122-0.pdf
57. Jones RJ, Dickerson S, Bhende PM, Delecluse HJ, Kenney SC. Epstein-Barr virus lytic
infection induces retinoic acid-responsive genes through induction of a
retinol-metabolizing enzyme, DHRS9. J Biol Chem. 2007 Mar 16;282(11):8317-24. doi:
10.1074/jbc.M608667200. Epub 2007 Jan 22. PMID: 17244623.
https://www.jbc.org/content/282/11/8317.long “Abstract: Lytic Epstein-Barr virus (EBV)
replication occurs in differentiated, but not undifferentiated, epithelial cells. Retinoic acid
(RA) induces epithelial cell differentiation. The conversion of retinol into its active form,
retinoic acid, requires retinol dehydrogenase enzymes. Here we show that AGS gastric
carcinoma cells containing the lytic form of EBV infection have enhanced expression of a
gene (DHRS9) encoding an enzyme that mediates conversion of retinol into RA. DHRS9
expression is also increased following induction of lytic viral infection in EBV-positive
Burkitt lymphoma cells. We demonstrate that the EBV immediate-early protein, BZLF1,
activates the DHRS9 promoter through a direct DNA binding mechanism. Furthermore,
BZLF1 expression in AGS cells is sufficient to activate DHRS9 gene expression and
increases the ability of retinol to induce the RA-responsive gene, CYP26A1.” (57)
58. CYP26A1 https://www.ncbi.nlm.nih.gov/gene/1592
59. Golden Milk - 10 Benefits and How to Make It. medicalnewstoday.com,
https://www.medicalnewstoday.com/articles/324181#benefits
60. Vijayaraghavan R, Gautam A, Flavonoid Treatment for Mustard Agents’ Toxicity.
intechopen.com,
https://cdn.intechopen.com/pdfs/36267/InTech-Flavonoid_treatment_for_mustard_agent
s_toxicity.pdf
61. Pomegranate Extract, ScienceDirect.com,
https://www.sciencedirect.com/topics/immunology-and-microbiology/pomegranate-extrac
t Excerpt from: Fascia: The Tensional Network of the Human Body, 2012.
62. Itika Arora, Manvi Sharma, Liou Y. Sun,Trygve O. Tollefsbol, The Epigenetic Link
between Polyphenols, Aging and Age-Related Diseases. Genes 2020, 11(9), 1094;
https://doi.org/10.3390/genes11091094 https://www.mdpi.com/2073-4425/11/9/1094/htm
 63. A Polyphenol-Rich Diet Prevents Inflammation in Older People,
Nuerosciencenews.com,June 8, 2022,
https://neurosciencenews.com/polyphenols-inflammation-20785/
64. "As mechanisms, we found that SARS-CoV-2 S1 protein exerted non-cell autonomous
hippocampal neuronal cell death by inducing interleukin-1 beta (IL-1β) expression
from glial cells." nature.com/articles/s41598-022-09410-7
https://www.

65. How Do Histamine Antagonist/inverse Agonists Work?

https://www.rxlist.com/how_do_histamine_antagonist-inverse_agonists_work/drug-class.
htm

🐭
66. Re Berberine, amyloidosis mentioned, it is an Nrf2 promoter Therapeutic properties of
Berberine - by DoorlessCarp (substack.com)
67. Toxic PFAS, the “Everywhere Chemicals,” Are in Organic Pasta Sauce and Ketchup,
Drugs, Pesticides, and Foodware. Sierra Club,
https://www.sierraclub.org/sierra/toxic-pfas-everywhere-chemicals-are-organic-pasta-sau
ce-and-ketchup-drugs-pesticides-and

End of Reference List