Topic: For MEDICALLY SAVVY RESEARCHERS ONLY PLEASE - understanding our response to Bb
Marnie
Frequent Contributor (5K+ posts)
Member # 773
posted
This is NOT intended to put anyone down or an ego-trip for me, but is an attempt to
share information/knowledge with others here who ARE interested in what Bb does to us and how our body responds.
I believe if we understand what is happening medically, we will be more likely to figure out a safe, effective and affordable CURE.
If you start talking to ME face to face about the stock market, you will be met with a blank stare. A bear market, a bull market, futures...are completely Greek to me...and I don't WANT to learn about the stock market...I just want it to make me rich! (It isn't.)
Most of you simply want to be told
what to do
to stop this horrific pain, this infection.
I understand!!!
We know how to destroy many pathogens, but not all of them...
Fungi are really hard to eliminate and the virus- HIV and the spirochete- Bb are so incredibly complicated we have yet to figure out how to destroy those (via "traditional" medicine)...but many people are working very hard to figure out the answer...the solution.
I, for one, think we are getting closer.
PLEASE, no personal attacks in response to this post.
Part one:
I am going to link you to one of the best websites to understand what is happening in lyme.
But first, I will talk you through the preceeding steps as I understand them.
Bb FIRST attacks the endothelial cells that line the blood vessels. Lyme starts out as a vascular disease. ``H16'' is the classification for vascular diseases.
Those endothelial cells are the first ones infected.
Next, we have roving ``policemen'' which are Langerhans cells/dendrite cells (DC) whose job it is to capture the infected cells and carry them away to ``present'' them to i.e., meet up with, other cells (T cells).
Along the way, the DC cells are supposed to begin the destruction, in order to present the pathogen's antigens (proteins) to the T cells.
The DC cells are the second ones infected.
Now we've got the T cells. T stands for thymus because that is where our WBC (white blood cells) go to ``mature'' and be made into the various kinds of white blood cells.
The T cells are the 3rd cells infected.
Side note here...removing the thymus gland stopped myasthenia gravis in someone I know who got THAT disease at a very young age - high school. He must now, however, take small doses of steroids the rest of his life. He went on to college, marry and father children and is perfectly healthy.
Okay...back to the T cells. They are the next ones infected with Bb.
Now for the link. Watch for *T cells activated* because that is when a receptor is initially activated...PPARy (= PPAR gamma).
Steroids downregulate PPARy = PPAR gamma (but there are 3 forms of PPAR gamma - y1, y2, and y3) Do steroids downregulate ALL forms of PPARy i.e., PPARy1, PPARy2 and PPARy3 or just one/two of them?
Our infected macrophages (a kind of WBC that ingests foreign materials) look to be metabolizing (breaking down) tryptophan to quinolic acid (LOTS - too much is being made).
Quinolic acid converts to niacin! Quinolinate transphosphoribosylase is the enzyme needed for the conversion of quinolic acid to niacin.
To see what is made during tryptophan metabolism (when quinolic acid "happens"), you can go to the following link if you want. Scroll down a little and look at the box that shows the
metabolism of L-tryptophan into serotonin and melatonin (left)
Bb needs niacin (to make NAD and NADP), but so do we! Does lyme disease -> a deficiency of niacin (along with so much more)? NAD participates in glycolysis (using glucose...a carbon chain ...to supply energy to make a LITTLE ATP).
The cells that Bb infects (our own defense cells) are making far too little ATP because they are functioning solely on glucose to make ATP, not using glucose + oxygen (which is called oxidative phosphorylation) to make a LOT MORE ATP.
PPARy (= PPAR gamma) signaling:
PPARy ``helpers'' (agonists) are used to treat insulin resistance.
The inflammatory cytokines are impacting insulin RELEASE. Bb is PFK dependent and insulin ACTIVATES PFK. PFK is phosphofructokinase and it is the RATE LIMITING enzyme for glycolysis.
``In vitro, cytokines like interleukin-1-beta (IL-1-B) and tumour necrosis factor-alpha (TNF-A)
inhibit insulin release and can destroy islet B-cells.''
Insufficient PPARy because the inflammatory cytokines inhibit insulin release which is needed to express PPARy (repeating...PPARy expression is generated by insulin).
Both oleic acid (in coconut oil) and VLA (valproic acid) look to activate PPARy.
But they inhibit different things:
VLA (valporic acid) looks to inhibit HDAC1 while Oleic acid looks to inhibit HDAC2.
HDAC = Histone deacetylases = REMOVE acetyl groups
And reducing the histone deacetylases (which removes acetyl groups) influences many genes.
"The nuclear receptor PPARy is implicated in the control of cell proliferation and apoptosis. However, the molecular mechanisms by which it controls these processes remain largely elusive.
We show here that PPARy activation in the presence of the retinoblastoma protein (RB) results in the arrest of cells at the G1 phase of the cell cycle, whereas in the absence of RB, cells accumulate in G2/M, endoreduplicate, and undergo apoptosis.
Through the use of HDAC inhibitors and coimmunoprecipitations, we furthermore demonstrate that the effects of RB on PPARy-mediated control of the cell cycle and apoptosis
depend on the recruitment of histone deacetylase 3 (HDAC3) to PPARy.
In combination, these data hence demonstrate that the effects of PPARy on cell proliferation and apoptosis are dependent on the presence of an RB-HDAC3 complex."
So if Bb is inhibiting HDAC1 and we can inhibit HDAC2 (via oleic acid) that would only leave HDAC3 (to remove an acetyl group from relA) which might de-activate that gene of Bb's.
Capase 3 is being upregulate to cleave RelA/p65. It is basically breaking apart that protein.
"Caspase-3-mediated ***cleavage of p65/RelA*** results in a carboxy-terminal fragment (COOH) that
inhibits IκBα. and enhances HIV-1 replication in human T lymphocytes."
So cleaving the RelA/p65 gene should be inhibiting NFkB, but it is not.
This maybe why:
(Like in HIV infected cells)
``In this study, the function of a caspase-3-mediated carboxy-terminal fragment of p65/RelA, which was detected in activated human peripheral blood lymphocytes (PBLs), was analyzed.
Cells producing this truncated p65/RelA did NOT undergo apoptosis but showed a high viability,
in spite of caspase-3 activation.
These data suggest the existence of a novel mechanism for maintaining NF-κB activity in human T cells
through the binding of the carboxy-terminal fragment of p65/RelA to IκBα in order to protect wild-type p65/RelA from IκBα inhibition.''
If we only allow HDAC3 and HDAC8 to work, HDAC3 removes an acetyl group from RelA/p65 on Bb AND on NFkB -> reduced NFkB? Turning off NFkB?
Backing up...a carboxy-terminal fragment of p65/RelA (even when it is cleaved by caspase 3) protects the cells from IkBa inhibition (which normally prevents the activation of NFkB).
What the heck is a carboxy fragment?
Interesting structure! Oxygen with a double bond and single OH bond.
In the above link about oleic acid... I just ``gotta'' mention this WEIRD fact:
``Oleic acid is emitted by the decaying corpses of a number of insects, including bees and Pogonomyrmex ants and triggers the instincts of living workers to remove the dead bodies from the hive. If a live bee or ant is daubed with oleic acid, it is dragged off as if it were dead.''
If HDAC3 works by removing an acetyl group on RelA/p65...what adds it on?
``...acetylation of RelA in vitro and in vivo after stimulation of cells with tumor necrosis factor alpha (TNF-α).
Coexpression of catalytically inactive mutants of the catalytic subunit of protein kinase A/mitogen- and stress-activated kinase 1 or IKK1/IKK2, which phosphorylate RelA on serine 276 or serine 536, respectively, sharply inhibited RelA acetylation on lysine 310.
Furthermore, phosphorylation of RelA on serine 276 or serine 536 increased assembly of phospho-RelA with p300, which enhanced acetylation on lysine 310.
Reconstitution of RelA-deficient murine embryonic fibroblasts with RelA S276A or RelA S536A decreased TNF-α-induced acetylation of lysine 310 and expression of the endogenous NF-κB-responsive E-selectin gene.
These findings indicate that the acetylation of RelA at lysine 310 is importantly regulated by prior phosphorylation of serines 276 and 536.
Such phosphorylated and acetylated forms of RelA display enhanced transcriptional activity.''
So...acetylation of RelA happens as a result of TNF alpha and acetylated forms of RelA *enhance transcriptional activity*.
IKK1/IKK2 phosphorylate (add phosphates on) RelA (a protein) on serine 276 and serine 539 which inhibits Rel acetylation on lysine 310.
``Mononuclear phagocytes play a major role in immune and inflammatory responses. Bacterial lipopolysaccharide (LPS) induces monocytes to express a variety of genes by activating the NF- B/Rel transcription factor family.
Recently, we have reported that the tumor necrosis factor and interleukin 1 signaling pathways activate two kinases, IKK1 and IKK2.
Phosphorylation of the I B cytoplasmic inhibitors, I B , I B , and I B , by these kinases triggers proteolytic degradation and the release of NF- B/Rel proteins into the nucleus.''
I'm going to try to piece the above together in sequence (untangle the information)..took me a lot of re-reading very carefully to do that!
A bacteria triggers monocytes to activate NFkB/Rel transcription via TNF alpha and interleukin 1 to activate 2 kinases = IKK1 and IKK2 (transfer phosphates to serines) -> phospho RelA which normally inhibits RelA acetylation (acetyl transfer) on lysine.
But if PKA (protein kinase A) is present at the same time as ILL1/IKK2, this inhibits RelA from acetylation (transfer of an acetyl) on lysine which would normally happen as phospho-RelA with p300 (another protein) enhances the acetylation on lysine 310.
First 2 phosphates are transferred -> phospho-Rel and then acetylation (acetyl transfer)to Rel A happens in the absence of PKA.
The phosphosphorylated AND acetylated forms of RelA ENHANCE TRANSCRIPTION.
Now...backing up...HDAC3 looks to REMOVE an acetyl group from RelA/p65.
RelA and SpoT of Gram-negative organisms critically regulate cellular levels of (p)ppGpp.
RelA (protein, gene) regulates the cellular ***level of*** (p) ppGpp.
(p) ppGpp appears to be a ``hey, this cell is starved for amino acids or glucose" signal.
It is a regulator of gene expression and survival.
``...upon fatty acid OR carbon starvation, SpoT enzyme activity switches from (p)ppGpp degradation to (p)ppGpp synthesis.'' (Glucose is a *carbon* chain.)
If glucose starved, Bb may upregulate SpoT to trigger ppGpp synthesis.
If fatty acid starved, Bb may upregulate SpoT to trigger ppGpp synthesis.
But PPARy, if present, maintains the BALANCE of lipids (fats - amino acids) AND glucose levels.
Does restoring the BALANCE of glucose and amino acids IN OUR INFECTED DEFENSE CELLS (via upregulating PPARy via oleic acid) allow them to once again work - do the job they are supposed to do?
Will it stop Bb from constantly altering its gene expressions?
To read how coconut oil (which contains oleic acid) is helping to REVERSE Alzheimer's disease, go here:
Oleic acid is also in olive oil (which I think we all know) is very good for us. It is used IN SYNERGY with chemotherapy to destroy breast cancer cells:
Once again, I believe it is vital to tame down the immune response AND hit Bb simultaneously.
I am very hopeful this Omega 9 (oleic acid) which activates PPARy will restore the balance of fatty acids and glucose and in synergy with abx. (perhaps) will help lyme disease patients too.
I would not expect miracles overnight. I suspect it will take time.
Do I think oleic acid alone could cure lyme? I don't know, but I am astounded by the results obtained from the use of coconut oil to reverse Alzheimer's Disease.
I am open to the exchange of information ..pro and con,and any corrections, but please try to document, link, your findings too if possible.
Ancora Imparo (translation: I am still learning)
Posts: 9424 | From Sunshine State | Registered: Mar 2001
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TerryK
Frequent Contributor (5K+ posts)
Member # 8552
posted
Briefly went through this - very briefly since I need to wind down and go to sleep. Need to be ready for my trip to LLMD.
Beautifully laid out. Thank you so much for all the effort you put into this.
Will spend time on this when I get back.
Terry
Posts: 6286 | From Oregon | Registered: Jan 2006
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Marnie - a physician told me recently that mast cells can also be involved in messed-up immune responses to Bb - have you researched their involvement at all?
Posts: 13117 | From San Francisco | Registered: May 2006
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About 2 years ago, before I was diagnosed with Lyme, I was put on Niaspan (high-dose Niacin) for slightly high VLDL cholesterol and slightly low HDL cholesterol.
A few days into treatment, I woke up in the middle of the night feeling like someone literally had a blowtorch on my face, not the usual flushing that I get.
I had a sudden urge to urinate, got up to go, couldn't walk, legs kept collapsing, dizzy, disoriented, whole body red and ON FIRE!
Do you think this had anything to do with this Niacin---Borrelia link that you mentioned?
Posts: 67 | From south jersey | Registered: Jun 2008
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posted
Marnie, I am very interested in what you've put together here, but do you mind backing up to the beginning and explaining why you think the Bb infection starts in the endothelium of our BVs, and if so, why DC cells would be the next to be infected?
It is my understanding that Langerhans cells are limited to the digestive tract and to the stratum spinosum of the epithelium.
Doesn't it make more sense that the immune response would begin in the lymphatic vessels?
Posts: 962 | From Charleston | Registered: Jan 2002
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Marnie
Frequent Contributor (5K+ posts)
Member # 773
posted
Langerhans cells...the where they are, etc.:
I linked info. today under my post to "Trevor"...ya know...sarcoidosis...
I'm beginning to find a lot of other diseases/problems for which "coconut oil" (oleic acid) is beneficial. We must really need it.
Robin, a number of our defense cells are infected...macrophages, mast cells, neutrophils, etc.
Mast cells are really a prob. 'cause of the length of time they normally hang around.
Carl, niacin...not all forms cause the "flush"....
"Niacin is converted to nicotinamide and then to NAD and NADP in vivo.
Although the two are identical in their vitamin activity, nicotinamide does not have the same pharmacological effects as niacin, which occur as side-effects of niacin's conversion.
***Thus nicotinamide does not reduce cholesterol or cause flushing,[1]***
although nicotinamide may be toxic to the liver at doses exceeding 3 g/day for adults.[2] Niacin is a precursor to NADH, NAD+, NADP+ and NADPH, which play essential metabolic roles in living cells.[3] Niacin is involved in both DNA repair, and the production of steroid hormones in the adrenal gland."
You are welcome. This is a JOINT effort. We gotta work together...everyone supplying a "puzzle piece".
Brain "exercise" is important too. Learning something new is healthy. We actually MAKE more neuro RECEPTORS when we learn. A doctor told me that.
Posts: 9424 | From Sunshine State | Registered: Mar 2001
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posted
Your "basement membrane" link was helpful to me in understanding where you are trying to go with this...thank you. Now it makes sense.
BTW, I saw your post in the other thread concerning sarcoidosis. Yep yep, googling coconut oil and bowel inflammation!
Posts: 962 | From Charleston | Registered: Jan 2002
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