Dr. Theoharides Presentation on the Comparison of Cromolyn Sodium to Luteolin for Mast Cell Stabilization
Denver Mastocytosis Support Meeting May 5, 2012
Triggers of mast cell degranulation: There are 50 molecules that can trigger degranulation of mast cells, just in the body. (Not including the daily triggers we have to avoid, etc)
Mediators released from mast cells…histamine, chymase, tryptase, growth factor, leukotrienes, chemokines, IL 1, IL 6, IL 8, GM-CSF, TNLF, VEGF…
2 Inhibitors for mast cells:
Alpha 1 antitrypsan, alpha 2 microglobulin
Carboxypeptidase and tryptase are only released when degranulation occurs. Degranulation is similar to when a hand grenade explodes, with the contents of the cell all exiting the cell membrane. The mast cells can still selectively secrete many other molecules, but the carbxypeptidase and the tryptase are only secreted when degranulation occurs…unless the cells are damaged.
IL 6 is tracked better with degranulation than tryptase.
Mast cells release 3 ‘sets’ of molecules:
1) Vasoactive (histamine, tryptase, VEGF VIP
2) Chemoattractant (IL1, IL8, LTB4)
Phases of healing:
Cytokines (found in mast cells) necessary for Th17 maturation: IL 6, TGFB
Th17-primary autoimmune cells found in rheumatoid arthritis
Mast cells in psoriasis releases IL-17
IgE antibodies specific for glactose-a-1, 3-glactose
As for enzymes taken orally, often enzymes get destroyed in the gut, like insulin can’t be taken orally, it wouldn’t make it through digestion.
Dr. Theo calls the mast cells the immune gate to the brain
The basal ganglia has as many mast cells as the skin.
Mast cells are located immediately around the blood vessels and nerves in the brain.
Tryptase …Dr. Theo calls it meat tenderizer.
Carboxypeptidase is a Lysosomes- like granules, it breaks down debris WITHIN cells
Carboxypeptidase would only be released from mast cells if the cells are damaged. Maybe carboxypeptidase is being released from OTHER cells, as a secondary reaction.
Mast cells talk to glial cells. Microglia is a tpe of immune cell in the brain
BPA (bisphenol –A) wreaks havoc on mast cells!!
Stress and its effect on mast cells:
Prenatal negative life events cause increased cord blood IgE…children are more allergic to dust mites.
Prenal stress increases the chance of having a child with autism by 4-6X
Rats weaned too early have more mast cells in their gut…more mast cells talking to their nerves
1st stress hormone released- CRH
-released into the brain and the body along nerve pathways
-HPA (hypothalamus, pituitary, adrenal) axis stimulation
Cortisol is human stress hormone, corticosteroid in animals
HPA Axis->cortisol secretion
c-kit receptor for stem cell factor
Mast cells have as many receptors for CRH as the brain!!!!
Stress stimulates the HPA axis
People trying to come up with CRH inhibitors
CRH augments allergic VEGF release from human mast cells
Stress can affect mast cells directly and indirectly and increase the number of receptors for CRH
Dec 2011- Mitochondrial function and Increased brain inflammation in BiPolar Disorder and other Neuropsychological disease
-15 independent studies showed 2 clusters of genes that stood out
Human Mast cell degranulation and preformed TNF (tumor necrosis factor) secretion requires mitochondrial translocation to exocytosis sites- relevance to atopic dermatitis
Margules mitochondrial evolution theory…mitochondria evolved from bacteria (now could have implications to our internal immune response, when the mito translocates outside of cells, since the body then sees foreign bacterial matter that it would have to manage)
Mitochondrial DNA detected in the supernatant fluid from the NT stimulated LAD2 cells
Sonicated mitochondria trigger human mst cells to release TNF and IL8
Substance P and Neurotensin 1 were discovered by Susan Lehman (researcher)
They are stored in the same neurons and secreted with CRH->meninges not as much as the hypothalamus
Neurotensin is THE strongest trigger of mast cells other than IgE
In autistic children, Increased levels of neurotensin in the brocha area of the brain , which controls speech. That area of the brain has more numbers of receptors for neurotensin…
The body turns into seterizine, so it crosses into the brain, slightly anti-anxiety, allows for deep sleep.
Periactin: Anti-histamine and Anti-serotonin
Migraines…or when a child complains of a stomach ache-they call that the migraine equivalent.
Zoditen->ketotifen: Antihistamine, Antieosiniphilic
Rupafin->Rupatadin: Antihistamine/anti PAF/strong Anti-eos
Gastrocom- mast cell blocker???
Cromolyn socium – blocks rat mast cells, but NOT HUMAN MAST CELLS
Allergo-Stop, topical being developed atarax and luteolin together in a cream mast cell blocker skin lotion
Oral absorption of quercetin and luteolin is LESS than 5%
Quercetin on the public market can be made from peanut shells or fava beans!!
For people with Mediterranean/Italian heritage, fava beans cause hemolytic anemia by releasing C6PD?
Lyposomes increase absorption to 20-25%
Luteolin blocks mitochondria-dependent allergic mast cells VEGF release
Luteolin blocks mito translocation from degranulation
Luteolin inhibits myelin basic protein induced human mast cells
CALCIUM STARTS THE DEGRANULATION PROCESS. When magnesium is present, the calcium degranulation process is inhibited.
He said that massive amounts of magnesium can have negative effects on health.
He has seen IgG IV for children working, particularly in the autistic community…
Scent and olfactory triggered mast cell degranulation:
The put allergen directly into the nasal area, took blood over 6 hour period and cortisol was secreted by that nasal exposure. In order to control for just the stress of not being able to breathe, they closed nostrils of control group with close pins…control group did NOT have cortisol release.
Luteolin is in artichoke
Oxidative Stress is a response to all stimulus
Glutathione and SAMe counter oxidative stress- glutathione doesn’t get absorbed very well, must be injected for more effective application
Resveratrol – good antioxidant, but NOT a good anti-inflammatory
Quercetin-good antioxidant AND anti-inflammatory (there’s no minimum age for quercetin, unless a premie with delayed liver development/compromised)
TedMed videos on Nature Drug Discoveries (need to look up)
4 Symptoms of overdose of H1/Anti-histamines
1) Retention of Urine
2) Dry Mouth
3) Hyperthyroxia->increase in temp up to 106 degrees!
4) *******THEY STIMULATE MAST CELLS AT HIGH DOSES!!!!*******
Also…10-50% get hyper
Steroids can cause anaphylaxis
Liver processes the metabolite of the histamine blocker that does the work…
****Proponolol and antifungals block the ability of liver to create the metabolite that allows the anti-histamines to work!!!
Linked together with heparin…if linked together, keeps tryptase active.
Trigger to cascade of inflammation:
Lyposome fuses with Calcium and delivers into cell
A research experiment had a collection of mast cells in two different containers-dropped calcium into one and magnesium into the other. The mast cells in the mag did nothing. The calcium triggered every mast cell it was in contact with, but not the others surrounding it, so there was no reaction TO ANOTHER reaction…
They are trying to figure out what regulates calcium inside the cell…Dandrolian sodium blocks calcium inside cells…
Nestle just created a health sciences institute and is working solely on medical foods.
Medical foods don’t need clinical trials to go on the market…botanical drugs must go through clinical trial
Dr. Theo has done 4 papers on mast cells and breast cancer-
There used to be the oncogene hypothesis, which is still the case in some cancers, but others have shown that the stroma (area around the cells) are the indication of the cancer than the cells themselves.
Cells macrophages, Tcells, mast cells and other inflammatory cells accumulate around tumors
20X more mast cells around breast tissue than anwhere else in body
They have found that the mast cells around breast cancer DON’T release TNF (tumor necrosis factor), but secrete vascular endothelial growth factor, which helps for blood flow to the tumor.
He said if we could figure out how to transplant some of the mast cells that are ‘turned off’ into people with masto…that would be great! J These mast cells literally act as a protective barrier to the cancer cells.
Dr. Theo has been involved with research with 30Hz penetrating mast cells, and the mast cells were stimulated…he said our cells are not necessarily tolerant of the wavelengths from all the electrical components we are surrounded by. He has several clients who get itchy and flare around computers. He mentioned old use of grounding screens on computers, he thinks grounding is a good idea. J
Fat generates precursors to mast cells…dendritic cells are precursors, and base of hair follicles have mast cell precursors…
Progesterone and testosterone inhibited mast cells
The flavonoids have been proven effective with prostate cancers-PSA levels went down VERY quickly!