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The Anti-Microbial Peptides
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Prof Trevor Marshall
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 Posted: Mon Jan 29th, 2007 17:16

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Maria Tollin, a doctoral student at the Karolinska Institute, has written a thesis "Antimicrobial proteins and petides in innate immunity". It has been published by the Karaolinska Institute, and is available online at URL
http://diss.kib.ki.se/2005/91-7140-270-5/thesis.pdf

There are some fascinating sections, particularly the section describing current (2005) knowledge about the protection of the fetus in the womb.

The overview of the antimicrobial peptides at pages 6-17 is also excellent reading.

I haven't read every word, but it seems a reliable and scholarly work.

Enjoy...:)
ps: remember that the VDR transcribes LL-37 (Cathelicidin). Maybe it transcribes the others, we don't know for sure yet...

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 Posted: Mon Jan 29th, 2007 22:39

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Thanks for the link Dr. Marshall.

I keep getting an error on the download page. Perhaps it's just my computer. However, this page with an abstract pops up for me. http://diss.kib.ki.se/2005/91-7140-270-5/ just in case anyone else has that problem.

I found this paper too that is short, but maybe not really easy to read. 5 pages.

The Role of Antimicrobial Peptides in Innate Immunity by Tomas Ganz

My question is; Are these AMP's good against intraphagocytic bacteria? quoted from Tollin's abstract, "They kill microbes by disruption of their membranes." Does she mean cell walls or the infamous biofilms or tubule membrane structures we know so little about?



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tickbite
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 Posted: Tue Mar 20th, 2007 14:21

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Dumb question. Of course they are.



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Prof Trevor Marshall
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 Posted: Tue Mar 20th, 2007 16:44

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Greg,
The thesis I linked in message 1 comes up OK for me. It is a PDF document.

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 Posted: Tue Mar 20th, 2007 16:47

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Works fine with me too.



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 Posted: Tue Mar 20th, 2007 18:18

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yeah, it works fine now. didn't for me the day you posted!!! :?

off the wall question:

I was reading "Putative...." paper today and thinking about this: "that the subject ARBs are affecting yet-to-be-determined metabolism in the human genome itself, and not in the bacterial genomes. More research needs to be done to totally preclude this possibility."

"the binding of host proteins by microorganisms may help them avoid recognition by the host immune system" In reference to microbial angiotensin II receptor. How are you feeling recently about this Trevor?

Thanks~ Greg 

 



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Prof Trevor Marshall
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 Posted: Tue Mar 20th, 2007 18:30

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Greg,
I am certain that the primary mode of action of Olmesartan is agonism of the human VDR, and the subsequent reconditioning of the human immune system.

I was conservative in that paper, and didn't claim Benicar as an agonist, but that had changed by Karolinska (as I collected more data) and now the molecular dynamics has firmly confirmed its remarkable similarity to 1,25-D in the VDR binding pocket (same residues, same hydrogen bonding, etc). Out of the pocket it is different in conformation, but my knowledge of the VDR has progressed to the point where I understand that only the top of the binding pocket is important, not the 'tail'.

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 Posted: Tue Mar 20th, 2007 18:37

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Hi Trevor,
I am interested in this as well. If the primary action of Olmesartan is as an agonist of 1,25-D in the VDR, then how does its action (on the immune system) differ from that of 1,25 D?
Ruth



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 Posted: Tue Mar 20th, 2007 18:53

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Benicar activates the VDR. That down-regulates the production of 25-D and accelerates the degradation of 1,25-D. At that point the concentration of 1,25-D no longer inhibits the other receptors, particularly PXR, Thyroid and Glucocorticoid, and the patient begins to get some relief.

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 Posted: Tue Mar 20th, 2007 19:00

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Trevor,

I guess it's still kinda hard to figure out if the idea that bacteria have affinity for angiotensin II in order for them (in one way) to avoid detection is a substantial claim yet? The whole Olmesartan being antimicrobial property thing.

Thanks for hanging out and answering questions!!:D

~Greg 



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Prof Trevor Marshall
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 Posted: Tue Mar 20th, 2007 19:08

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I am sure that olmesartan is active in some of the microbes. The early 1990's research on ARBs identified that fact. I am not sure what exactly the effect on the microbes is, if any. I don't think it is direct killing, as the difference we see between folks' reaction to Benicar are now being readily quantified in terms of their D metabolism (by both myself and Dr Greg Blaney).

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 Posted: Wed Mar 21st, 2007 05:33

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Does VDR receptor can be modulated only in 3 ways ?
I mean is it only antagonism, agonism and partial-agonism ?
And what is partial-agonist/agonism difference ?

Or maybe are there other types of activation level,different partial activations etc.

I just would like to know if things are not more complicated than i think they are :)

I wonder if Benicar activates the VDR in the same way as 1,25-D, and only the difference is angiotensin II receptor affinity. Or maybe Benicar activates VDR in a different way than 1,25-D.

Last edited on Wed Mar 21st, 2007 08:22 by wrotek



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 Posted: Wed Mar 21st, 2007 10:39

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I don't think it is direct killing, as the difference we see between folks' reaction to Benicar are now being readily quantified in terms of their D metabolism (by both myself and Dr Greg Blaney).
 
Am I understanding this correctly?  Does the above mean that the higher the level of 1,25 D, the bigger the immune reaction from taking Benicar?  Or am I just missing the whole thing?  I DO understand that it's not a reaction TO the Benicar, but instead to the effect the Benicar has on the immune system.  (Just trying to figure out why I have had such a whopping reaction on Benicar alone, without ABX.:))

Carol



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 Posted: Wed Mar 21st, 2007 11:29

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Wrotek...look at the graph. Oh, and remember, things are always more complicated than we know. There's always a bigger fish.

Trevor, forgive me but I was under the impression that ARB's were competative antogonists. Basically dampening 1,25D amongst the nuclear receptors which thereby provided a mode of relief. The only ligand which activates the VDR is 1,25D correct?

~G 

http://en.wikipedia.org/wiki/Image:Antagonist.png

http://en.wikipedia.org/wiki/Image:Agonist.png 

Last edited on Wed Mar 21st, 2007 11:37 by tickbite



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 Posted: Wed Mar 21st, 2007 13:07

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Trevor,

Do you propose that when Olmesartan is ‘docked’ into the VDR that different coregulatory proteins are recruited (to the VDR-ligand complex) than when 1,25 is the docked ligand? And, if that is true, that the result is a possibly gene- and tissue-specific difference in transcription by the VDR?  Thus, Olmesartan may restore (up-regulate) transcription of the feed-back loop that is supposed to repress 1,25-D production when it is elevated?   Still working on this one ...

Ruth



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 Posted: Thu Mar 22nd, 2007 03:30

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Greg, as I understand it, Beni is an agonist, activates the VDR, thereby activating innate immunity. I don't know if the same goes for the other ARB's.

Carol, the difference might be the length of time one has been infected, or the type(s) of bacteria. Some will benefit (herx) greatly by 'just' activating innate immunity via VDR like you and Ellen and if I am not mistaken, our very own Barb.

Others won't herx until the abx are introduced.

Trevor posted a paper about MRSA some time ago, where they found that MRSA's resistance lies in the so called biofilm. The 'tube' the bacteria build around themselves to protect them from attack by the immune system.

This biofilm is created from 'bricks' called proteins.

One of the things the abx of the MP do, is hamper the protein-making by the bacteria, which will slowly lead to degradation of this biofilm, leaving the bacteria 'exposed' to the immune system once the biofilm doesn't protect them anymore.

Hope this helps a little.

Sincerely, Frans



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 Posted: Thu Mar 22nd, 2007 07:32

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Thanks Frans, it helps alot.  I have suspected it was length of time more than anything else.  But maybe the protein on the shell of the bug, or something as yet unknown about the individuality of immune systems has something to do with it, but I know that's getting into the area of my over zealous imagination.  :) 

My immune system does not shut off quickly either, even after Benicar is stopped.  (Which I realize has been stated as a possibility, on the site.)  I am happy that at least my immune system is still so responsive. 

Carol



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 Posted: Thu Mar 22nd, 2007 09:47

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I believe Olmesartan acts as a partial antagonist. The concentrations we use for Olmesartan competes with other antogonists and basically 'wins-out'. Because it is a partial antagonist (Ki ~ 10nM), Olmesartan still allows the VDR to be activated by 1,25D. http://en.wikipedia.org/wiki/Image:Antagonist.png

A stronger ARB like Telmisartan (Ki ~ 0.04nM) would come close to shutting down the VDR totally. Ruth brings up a very interesting hypothesis. Heck, maybe i'm absolutely confused............:?

"1,25-D is the only metabolite that turns the VDR on.
Everything else turns it off, or at least modifies its capabilities. So exogenous Vitamin D and 25-D both bind into the VDR and block it from working properly. They will displace any 1,25-D from the receptor in a dose-dependent manner. The higher the concentration of Vitamin-D or 25-D competing with the endogenous 1,25-D the more of that 1,25-D will be displaced from the VDR. That occurs in a manner represented by the displacement graphs in the FDA presentation.

Benicar also stops the over-excitation of the VDR by inactivating it, but it does so in a dose-dependent and controllable manner. We control Benicar's activity against the VDR by varying the Benicar dose. But Benicar also has profound actions elsewhere in the immune system. Some I am already aware of, some I am not.

..Trevor.."

Dr Marshall's paper on molecular modeling describes the effect of ARBs (and the superiority of Benicar at the appropriate dose) on the nuclear receptors of the immune system:

Research    
Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b
Trevor G Marshall, Robert E Lee, Frances E Marshall
Theoretical Biology and Medical Modelling 2006, 3:1 (10 January 2006)
[Abstract] [Full Text] [PDF] [PubMed] [Related articles]


 

Last edited on Thu Mar 22nd, 2007 09:54 by tickbite



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 Posted: Thu Mar 22nd, 2007 10:35

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Although I have been around for years reading about VDR and all it's ilk I finally had to admit I still don't understand it all.

I took a look around and noticed that answers.com has some really nice (short) articles on all of the things we talk about here.  (With many links to OTHER things you can't quite understand built into each article).  I am sure a lot of folks would be happy to read some of this and finally say 'AHA  so that is what Trevor is talking about".

Also once you understand this, you can then go and direct your immune system to 'just do it'  :D

http://www.answers.com/topic/receptor


http://www.answers.com/topic/messenger-rna


http://www.answers.com/topic/transcription   (AKA rna_synthesis)


http://www.answers.com/topic/dna-synthesis

 

Last edited on Thu Mar 22nd, 2007 10:36 by Jimbbb



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 Posted: Sun Mar 25th, 2007 08:03

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Greg,

Benicar really is an agonist of the VDR, the qoute you give is an old one. Trevor's views have evolved past the last paper.

See: - http://tinyurl.com/2xdpws

Best, Frans



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 Posted: Sun Mar 25th, 2007 11:09

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Am I just going insane? :) I'm sorry Frans, your link is just reiterating this thread....

This paper:

Research    
Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b
Trevor G Marshall, Robert E Lee, Frances E Marshall
Theoretical Biology and Medical Modelling 2006, 3:1 (10 January 2006)
[Abstract] [Full Text] [PDF] [PubMed] [Related articles]


says that olmesartan is an antagonist...........it uses the word agonist one time to reference a researcher who thought that telmisartan was both an agonist and an antagonist. That's it...........the word agonist and olmesartan never come together in one sentence. Are we saying this 1 year old paper is just phooey?

I guess when anyone has time I would greatly appreciate a clarification. Someone please read the paper and see what i'm talking about! Would someone also clarify the difference between a 50% partial agonist and a 50% partial antagonist? Is that what i'm crazily arguing over here? :X

If it is true that beni is an agonist, then Ruth's question above i would love to see the answer to.

 



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 Posted: Sun Mar 25th, 2007 11:53

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As far i know benicar activates VDR, other things else diactivate receptor, like 25-D, so these are antagonists.

Only agonists activate things.

The is no term 'partial antagoinst' because there is a term 'partial agonist', which means some part is activated and some is not. So, partial antagonist is unnecessary term, potentially confusing, because it would mean the same thing - some part is activated and some is not activated, just like in case of 'partial agonist'.

I wonder also if this following example is correct.
We have keys that fit one particular lock.
But only one key can be "twisted" and open the lock, and this would be agonist. Some keys twist in the lock but do not open the lock and these i would call 'partial agonists'. Some keys only fit the lock, do not twist and are antagonists which block the lock.

I am concerned by quotes from Tickbite's statement from paper Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b

Telmisartan was predicted to strongly antagonize (Ki≈0.04nmol) the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki≈10 nmol) are likely to be useful VDR antagonists

or
The Ki = 12E-9 configuration of Olmesartan (Figure 7), forms a hydrogen bond from its imidazole terminal hydroxyl to ARG274. Olmesartan forms only hydrophobic contacts with the key VDR binding residues TYR143, SER237, SER278 and HIS305. TYR143 is especially important. It is part of the 'hinge region,' and key for VDR transcriptional activity [51,57]. It is thus almost certain that Olmesartan will function as a VDR antagonist.


Last edited on Sun Mar 25th, 2007 12:32 by wrotek



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 Posted: Sun Mar 25th, 2007 13:34

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yeah! thankyou for seeing what i'm talking abot wrotek! for a second I thought maybe i was totally delusional and literally insane.........

Not that I'm a bonafide researcher, however I can read. I have read that the definitions of agonism and antagonism are becoming blurred.

Simply read the above paper put out by Dr. Marshall and you'll see what I mean.

If benicar "activated" the VDR then we should deduce that benicar also acts as 1,25D which would in fact be TERRIBLY BAD. Why would we want to supplement benicar if it acts as 1,25D?????????????? We wear NoIR's and cover up to redcue 1,25D being created..............inflammation is bad.

For real......

 



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 Posted: Sun Mar 25th, 2007 13:55

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Dunno :). The interesting thing is we don't want immunosupressive 25-D be present in too high quantities in a body, and we don't want 1,25-D be too high also. So reducing 1,25-D by reducing 25-D ingestion should make things start working properly again in some point.

But, maybe we can't stabilize this 'point' and we need certain VDR activation level that can be achieved by 40mg Benicar dosing every 6 hours which we do, because we can't control Vitamin D metabolism tight enough, except reducing it as much we can by light restrictions and reduction in vitamin D consumption .

Last edited on Sun Mar 25th, 2007 14:21 by wrotek



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 Posted: Sun Mar 25th, 2007 14:35

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In light of the fact that Dr. M's paper as resourced above documenting Olmesartan's (benicar) antagonist activity, my conclusion is that Benicar allows activation (agonization) to happen because of the concentration at which the ligand is taken and because of the affinity which the ligand produces. In consequence, because of my lack of education of the subject my poor brain will relegate benicar's affects as antagonistic. If I am to think that 1,25D and Benicar are similar and activate the VDR, then why are we adding 1,25D like substance which would "...allow the bacteria to colonize the phagocytes, avoiding the lysosomal phagocytosis.

Clearly this is not the case. Benicar's actions are far more diffucult to describe as being purely antagonistic or agonistic.



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 Posted: Sun Mar 25th, 2007 16:57

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Have you seen this new research - I don't think there is any debate that Benicar actives the VDR

http://www.marshallprotocol.com/forum39/8573.html

But like you conclude, it is over simplifying to say that it behaves just like 1,25-D throughout the body. Then it would make us sick, not better.

All the science I don't understand ....... it's just my job five days a week

Last edited on Sun Mar 25th, 2007 17:00 by MarkN



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 Posted: Sun Mar 25th, 2007 19:22

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:( yep, seen it and looked at it wiggle for a long time......I'mhonestly not trying to debate. I'm trying to understand why benicar went from being explained as an antagonist to agonist. What happened and why?



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 Posted: Sun Mar 25th, 2007 21:13

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When the VDR is activated the gene for CYP24 is transcribed. This enzyme breaks down 1,25-D to inactive 24,25 and 25,26-D. This is one of the feedback control mechanisms keeping the level of 1,25-D at optimum.

So, Benicar activates the VDR and forces 1,25-D out of it. The CYP24 is transcribed, and the level of 1,25-D is thus reduced. Several patients have measured this reduction during the first few days of Benicar use.

1,25-D is no longer so high in concentration, no longer able to go after the Thyroid and Glucocorticoid receptors, the eye retina, and no doubt many other places I haven't fully figured out yet. Benicar has little affinity for most of those other receptors, as Benicar is structurally different from 1,25-D. The displacement of 1,25-D from being 'the control freak' thus reduces the 'hypervitaminosis D' symptoms.

The bugs have some way of defeating the control loops, which is what allows the 1,25-D level to rise to very high levels in the first place. My best guess is that one or more bug proteins bind to the chromatin or VDR or SRC1 in such a way as to inhibit the transcription of the CYP24 gene...

There is also a possibility that the 1,25-D concentration is lowered by the PXR receptor failing to transcribe the CYP27A1 gene. Benicar is a PXR antagonist, but so is 1,25-D (another control loop). I think this is less likely right now, but maybe next week I will have a different perspective:)

ps: sorry I wasn't around, have been travelling the last few days.

Last edited on Sun Mar 25th, 2007 21:23 by Prof Trevor Marshall

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 Posted: Fri Apr 27th, 2007 11:57

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Ruth Goold wrote: Trevor,

Do you propose that when Olmesartan is ‘docked’ into the VDR that different coregulatory proteins are recruited (to the VDR-ligand complex) than when 1,25 is the docked ligand? And, if that is true, that the result is a possibly gene- and tissue-specific difference in transcription by the VDR?  Thus, Olmesartan may restore (up-regulate) transcription of the feed-back loop that is supposed to repress 1,25-D production when it is elevated?   Still working on this one ...

Ruth
Good question........



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 Posted: Fri Apr 27th, 2007 12:40

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Ruth,
The mechanism is simpler than that.
I have just written a review paper (which will hit print later this year) which explains it all in some detail, but briefly, if you were a persistent intracellular bacterium it would make sense for you to want to evade the immune system. Imagine your surprise when you found you could knock out both the Cathelicidin and beta-Defensin anti-microbial defenses by blocking the operation of just one receptor, the VDR!

When you block the VDR you interrupt the down-regulation of the production of 1,25-D (via the CYP27B1 and CYP24A1 metabolisms), and therefore the level of 1,25-D rises to dangerously high levels. This in turn depresses the transcription of CYP27A1 by the PXR receptor, lowering the level of generated 25-D, but that doesn't worry you either (the bug).

However, the high level of 1,25-D also interrupts the PXR receptor transcribing a number of Xenobiotic enzymes (detoxifying enzymes)(pXr) as well as CYP27A1. This is not good for the safety of your host. The high 1,25-D levels also stop the Thyroid and Glucocortiocid receptors from working properly, as well as GPCRs in, for example, the retina (Rhodopsin). But again, this doesn't affect the bacterium, only the host. The trick is to make sure the host just stays pretty sick, but doesn't die...

It would be a neat plan of action, don't you think? The only problem might arise if a VDR agonist happened on the scene, capable of displacing your ligand from the VDR, making the VDR work properly again, and restart transcription the genes producing those nasty anti-microbial thingys...

..Trevor..

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 Posted: Fri Apr 27th, 2007 13:36

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So the bacteria are likely producing a ligand that is a VDR antagonist and displaces 1,25D from the VDR thus blocking operation of the VDR and causing all sorts of problems (increased levels of 1,25D, no Cathelicidin and beta-Defensin production, etc.).  We then take Benicar, a VDR agonist, which is capable of displacing the bacterial ligand from the VDR. thus restoring VDR function.  Is that right?



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 Posted: Fri Apr 27th, 2007 14:51

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I wanted to ask the same thing :) - Do we know, what bacterium uses to block vdr. I thought Benicar is an antagonist, like MP papers say.

Last edited on Fri Apr 27th, 2007 15:11 by wrotek



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 Posted: Fri Apr 27th, 2007 15:16

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Wrotek,
Our early papers say Benicar is an antagonist because 99% of molecules antagonize, and less than 1% activate receptors. So you always start from that perspective (an atagonist unless proven otherwise).After about 6 months of exploring all the possibilities, you will note that my description changed around the middle of last year. Now that we have produced the Molecular Dynamics videos/data, definitely showing the actions of an agonist, probably a super-agonist, I now know exactly how Olmesartan, 125-D, and 25-D, function in the VDR.

Additionally, discovery of VDR genomics are ongoing, with one paper a day going into Pubmed. We have just managed to fit together a number of recent pieces of the metabolism puzzle (the 'big picture'), and the new chart has gone into our most recent review paper (which will be published later this year). Maybe the new chart will go online in a day or two, as it formed part of a presentation Meg, Belinda and I made to the FDA in Washington, just yesterday. Keep an eye on the forums for a report on that meeting...

ps: Russ - yes:)

Last edited on Fri May 4th, 2007 08:05 by Prof Trevor Marshall

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Now it is so clear for me thank You. (,^^) Before i thought that using some kind of antagonists level manipulation one can activate receptor somehow.



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 Posted: Fri Apr 27th, 2007 16:02

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Trevor, Russ, Wrotek,

Thank you, thank you, thank you. How nicely this deals with that aspect of the MP that has been most difficult to understand and explain to others - how olmesartan - a VDR agonist - restores innate immune gene transcription while 1,25-D - also a VDR agonist - does not.

Have you characterized the bacterial ligand? Is it specific to CWD bacterial forms? Or do extracellular bacteria have the ligand but get picked off by the aquired immune system eventually even if they do manage to compromise the innate defenses?

Ruth



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 Posted: Fri Apr 27th, 2007 16:33

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I wonder if some antidepressants may be a VDR agonists.

Last edited on Fri Apr 27th, 2007 16:34 by wrotek



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Wrotek,
I can assure that VDR agonists are very rare, and that antidepressants work on other parts of the immune system.

Ruth,
I haven't characterized the bacterial ligand, although it clearly is pretty active if it can displace 1,25-D from the receptors. We need a high concentration of Olmesartan to displace the ligand. The MD calculations indicate about a 1 nanomolar affinity for the stabilized Olmesartan in the VDR LBP. In-vivo we use a concentration of Olmesartan much higher than 1 nanomolar, so the affinity of the bacterial ligand must be quite high indeed, enough to also overcome the binding of 1,25-D into the VDR LBP.

..Trevor..

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 Posted: Sat Apr 28th, 2007 01:23

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I know it's more complicated than this, but sounds like the various affinities these molecules have for the VDR could be expressed as...

benicar (40mg x 4) affinity > bacterial ligand affinity > 1,25D affinity

Do you think that 1,25D levels ever rise high enough (maybe in the skin cells following sun exposure) so that in some cells 1,25D is able to displace the bacterial ligand from the VDR in the same manner as high-dose Benicar? 

I know that elevated 1,25D levels have very bad negative effects (due to actions on other receptors) that high-dose Benicar does not have, but I'm curious if, at high enough levels, the action of displacing the bacterial ligand from the VDR would be the same.

Last edited on Sat Apr 28th, 2007 01:38 by Russ



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 Posted: Sat Apr 28th, 2007 05:45

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Russ,

i've spoken to many a sun addicted Th1 sufferers.......My own previous experience is the same ~ I get out in the sun (shirt off, no glasses) and I feel great, 48 hrs later I feel like a ton of you know what. This suggests to me that generating high enough 1,25D will tempprarily displace anything out of the VDR LBP.

Trevor,

The "over-exuberant" VDR explanation wasn't well understood by me.  I had no idea how you were characterizing that. I guess now you don't. The "bacterial ligand" comes as a surprise to me, but then again that makes more sense. On a molecular scale wouldn't the "bacterial ligand" look like a steroid? If so, could we run genome symmetry sweeps of similar structures? sorry to sound like wrotek :)

~Greg

Last edited on Sat Apr 28th, 2007 05:53 by tickbite



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tickbite wrote: The "bacterial ligand" comes as a surprise to me, but then again that makes more sense. On a molecular scale wouldn't the "bacterial ligand" look like a steroid? If so, could we run genome symmetry sweeps of similar structures? sorry to sound like wrotek :)

~Greg



Hmm, this bacterial ligand is indeed a surprise, I was still thinking 25D was the bad guy in this respect, especially since we measure it in nanograms instead of the picograms in which we measure 1,25D. A thousandfold I thought, making the balance between 25D and 1,25D precarious indeed, considering their respective affinities.

Sincerely, Frans



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Dr Trevor Marshall wrote: We have just managed to fit together a number of recent pieces of the metabolism puzzle (the 'big picture'), and the new chart has gone into our most recent review paper (which will be published later this year). Maybe the new chart will go online in a day or two, as it formed part of a presentation Meg, Belinda and I made to the FDA in Washington, just yesterday. Keep an eye on the forums for a report on that meeting...

ps: Russ - yes:)


Can't wait !!  :D

Have you been able to do some business with the FDA? Meaning perhaps some funding ?

Frans



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 Posted: Sat Apr 28th, 2007 06:56

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Frans,
The relative concentrations of 25-D and 1,25-D in the phagocyte cytoplasms is much closer than 1000:1, most estimate the 1,25-D level in the cell to be about 1-2 nanomolar. It is diluted when it enters the bloodstream. This is the difference between measuring 'paracrine' and 'endocrine' concentrations. Additionally, 25-D in the cytoplasm is mostly (95%) bound to the DBP (D-Binding Protein), and not free.

The over-exuberant response was a very early idea. We have a much more accurate understanding of the steps in the metabolism now. Most all of the grey areas are now well understood, but there stilll may be some refinement of understanding as we move forward.

Russ, the formula for displacement vs concentration is on the slide from my FDA presentation which shows the displacement curves - take a look at that presentation again.

The bacterial ligand could be a sterol, a steroid, or it might be a very simple molecule, like ketoconazole. I have been trying to figure out how to look for it in the genome, but I don't have solutions yet. Many small molecules produced by living organisms are the result of enzymatic action, and that cannot easily be predicted.

The bacterial ligand hypothesis has become more and more likely as the genetic transcription behind more of the D-metabolism became defined. At this point it is (IMO) the only viable hypothesis which matches up with our clinical data.

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 Posted: Sat Apr 28th, 2007 08:49

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When you block the VDR you interrupt the down-regulation of the production of 1,25-D (via the CYP27B1 and CYP24A1 metabolisms)

Then, actually when we consume any ligands that block VDR (like Chlorogenic Acid), we simultaneously Increase 1,25-D level and make symptoms worse.
I wonder if Chlorogenic Acid may accumulate.

Last edited on Sat Apr 28th, 2007 08:59 by wrotek



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 Posted: Sat Apr 28th, 2007 09:22

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tickbite wrote: Russ,

i've spoken to many a sun addicted Th1 sufferers.......My own previous experience is the same ~ I get out in the sun (shirt off, no glasses) and I feel great, 48 hrs later I feel like a ton of you know what. This suggests to me that generating high enough 1,25D will tempprarily displace anything out of the VDR LBP.


I experience the same thing following sun exposure.  But I always thought the symptoms experienced due to increased 1,25D from sun exposure (faitigue, etc.) were due to 1,25D acting on the other receptors it hits like the glucocorticoid receptors and alpha-1 thyroid receptors, receptors that it is not supposed to hit so hard and only does so in these diseases where 1,25D gets so elevated.  If symptoms from sun exposure were instead the result of 1,25D displacing the bacterial ligands from the VDR, that would seem to imply that the symptoms are due to increased bacteria killing since my understanding is that 1,25D binding into the VDR is what is supposed to happen in a healthy immune system and would only cause negative symptoms if "turning on" more VDR receptors resulted in more bug killing.  My guess is that most of what we experience following sun exposure is due to the former (1,25D hitting the glucocorticoid receptors and alpha-1 thyroid receptors) but am curious if any might be due to the latter. 

Last edited on Sat Apr 28th, 2007 09:22 by Russ



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 Posted: Sat Apr 28th, 2007 11:38

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Russ,
I think it all depends how sick you are, how heavy the bacterial load is. Thus the symptoms become part of the chronic disease progression, something to which you adapt..

People who are not really, really, ill still have innate immune system function. IMO, those who are ill enough to get a diagnosis have lost most all VDR function to the pathogens.

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 Posted: Sat Apr 28th, 2007 13:15

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Dr Trevor Marshall wrote: The bacterial ligand could be a sterol, a steroid, or it might be a very simple molecule, like ketoconazole. I have been trying to figure out how to look for it in the genome, but I don't have solutions yet. Many small molecules produced by living organisms are the result of enzymatic action, and that cannot easily be predicted.

The ligand must be quite popular amongst bacterial genetics. What would it mean to be able to identify the genes responsible for the production of the ligand? in other words, how would that help us? Would it reinfornce the ideas of why we use targeted ribosome abx of the MP? or perhaps more?



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 Posted: Sat Apr 28th, 2007 13:21

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If we identify the genes responsible for the ligand we could design a drug to block those genes, prevent the production of the ligand, and save the world:)

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 Posted: Sat Apr 28th, 2007 13:34

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Would a drug that blocked those genes be a better treatment than the current method of benicar and antibiotics?  Wouldn't there still be immunopathology from killing the bacteria and therefore one could not progress any faster than we are currently?



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 Posted: Sat Apr 28th, 2007 13:42

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Russ,
The liklihood of us tracking down that gene(s) in the next 5 years is zero. In the next decade it is still close to zero. Focus on what we know right now and you will be enjoying life long before any 'breakthroughs' occur.

The "magic bullet" will in any case still produce immunopathology in folk already carrying a bacterial load.

I see no way to reduce the immunopathology. But there are a lot of folk who are thinking about ways of doing it, and we chat every now and then:):) It is unlikely we will come up with any therapy much better than we have now.

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 Posted: Sat Apr 28th, 2007 16:48

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Dr Trevor Marshall wrote: If we identify the genes responsible for the ligand we could design a drug to block those genes, prevent the production of the ligand, and save the world:)

I'm laughing now, but i'll be laughing a lot harder when this is all over!



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 Posted: Sat Apr 28th, 2007 19:13

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Glad you recognized the joke, Greg:)

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Rather than unblocking the VDR and fixing the real problem by getting innate immunity to function again, it seems you just need to scramble up a few polymers for breakfast:
    http://tinyurl.com/2x99dk



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Sure - in your dreams:):)

Madison are the people who wrought Vitamin D upon the world. Do you really want to allow them to wreck it totally?
 

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Unfortunately there seems to be no shortage of people out there who do :(, but the truth will out in the end :cool:



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Nick n Trevor,

So is it safe to say that the "Random Polymers" are acting like a super Beta-Lactam ABX.   (acts on the membrane of the bacteria it said).   I wonder if it would drive the bacteria into the L-form state as well?



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 Posted: Fri Dec 7th, 2007 07:54

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Jim,
Heaven only knows how they are acting. It is hard enough to analyze interactions with small molecules, let alone large ones.

There are tens of thousands of proteins produced by the human genome. These new polymers only need to interact in an unpredictable way with one of these proteins in order to cause disaster.

The FDA is mindful of Thalidomide, which was safety-tested with one isomer predominating, but in the human body another isomer was produced by enzymatic action. Everybody knows the result of that little slip-up:(

I cannot believe that any sound minded project leader would allow claims like this to be made so early in a project like this. I guess its all about getting more grant money for the University these days, isn't it... Sigh...
 

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 Posted: Wed May 28th, 2008 11:53

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Hi all,

I’d like to form a clearer understanding of how (and why) bacteria affect 1,25D.

It makes perfect sense that bacteria would produce substances that block VDRs (Capnine) thereby reducing AMPs (Anti Microbial Peptides) and improving their chance of survival.

It’s also logical that our bodies would then increase 1,25D to active the depleted number of available VDRs, in an attempt to increase the immune response against these invaders.

However, the Vitamin D Tutorial states that bacteria release interferon gamma which results in increased 1,25D. This seems to suggest that bacteria are directly stimulating the production of 1,25D which would increase production of AMP’s and decrease their survival chances. This appears to be rather counter intuitive.

Question: Do CWD bacteria directly stimulate 1,25D production OR are increased 1,25D levels just a by product of infection?

Cheers,
Chris :)



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 Posted: Wed May 28th, 2008 15:01

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bacteria indeed lead to upregulation of 1,25D, which would be the normal way our bodies get rid of the bacteria

MP is founded on the basis that the bacteria survive this initial onslaught

the problem then gets bigger and bigger as the bacterial load gets higher and higher, this will competitively displace 1,25D from the VDR, disabling it more and more, leading to lower AMPs etc.

the higher levels of 1,25D are there, but are just not high enough to get capnine, 25D and other antagonists out of the way and activate the VDR

the bacteria win the competition...

Hope this helps, Frans



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 Posted: Wed May 28th, 2008 16:54

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Maybe benicar does not affect other nuclear receptors just like 1,25-D does, so it activates VDR without side effects resulting from antagonism of other nuclear receptors.  It is more selective nuclear receptor agonist ?

Last edited on Wed May 28th, 2008 16:55 by wrotek



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 Posted: Wed May 28th, 2008 17:06

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Figure 1 of my "Vitamin D Discovery outpaces FDA decision making" is what you need to study. You will see that both Interferon gamma positive driving of P300/CBP trasncription of CYP27B1, and the lack of VDR transcription of CYP24 to degrade activated 1,25-D are contributors to the elevated 1,25-D levels due to this microbiota. There are other effects as well, but undersatnding those two is a good start...

http://TrevorMarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf
 

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 Posted: Wed May 28th, 2008 18:07

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 Frans wrote:the problem then gets bigger and bigger as the bacterial load gets higher and higher, this will competitively displace 1,25D from the VDR, disabling it more and more, leading to lower AMPs etc.

the higher levels of 1,25D are there, but are just not high enough to get capnine, 25D and other antagonists out of the way and activate the VDR

the bacteria win the competition...

Hope this helps, Frans


 

If the scenario above, as presented by Frans, is correct what is the general consensus to the following thoughts:

Item 1
Isn't capnine (like 1,25D and 25D) a key marker of Th1 chronic inflammation?   And if so, is there a Quest or Labcorp test to check capnine tissue levels? 

Item 2
Could the "floaters" that appear so commonly in the eyes of Th1 patients actually be biofilm elements?  And if so, simple visual evidence of the condition?

Item 3
Is capnine the greater antagonistic culprit and, if so, does that shift the therapeutic level of 25,D of <= 12 ng/mL upwards?  And the degree, of course, of emphasis on dietary intake of VitD and sunlight avoidance?   

TikBitten




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Thanks for your feedback Frans, Wrotek & Trevor,

1.) After reading up on Interferon gamma and "Vitamin D Discovery outpaces FDA decision making" I’ve reached the conclusion that... the rise in 1,25D is the body’s response to infection.

As far as we know the microbiota are NOT directly attempting to stimulate 1,25D as this would reduce their chances of survival. Please correct me if I’m wrong.

2.) However, as 1,25D reaches very high concentrations it blocks other receptors thereby reducing production of other AMP’s.

Is there any evidence that 1,25D is of benefit to the invaders at the lower concentrations?

Thanks again,
Chris :)



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 Posted: Fri May 30th, 2008 04:26

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Chris said:
the rise in 1,25D is the body’s response to infection
Indeed. If you look at Figure 1 in "Vit D discovery..." you will see Interferon-gamma as input to the upregulation of transcription of CYP27B1. In a healthy individual this would upregulate 1,25-D; upregulate VDR transcription, and enhance innate immune response. The metagenome has evolved to thwart that action by blocking VDR.

That is the reason that I talk about "Th1" disease - Interferon-gamma is the common thread in all these symptomatic variations, and IFg implies Th1 (by definition).
 

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http://www.nature.com/nature/journal/v463/n7279/full/nature08698.html
Nature 463, 369-373 (21 January 2010) ...Accepted 24 November 2009
Thomas Becker1, et al..

An important class of immune effector molecules to fight pathogen infections are antimicrobial peptides (AMPs) that are produced in plants and animals1. In Drosophila, the induction of AMPs in response to infection is regulated through the activation of the evolutionarily conserved Toll and immune deficiency (IMD) pathways2. Here we show that AMP activation can be achieved independently of these immunoregulatory pathways by the transcription factor FOXO, a key regulator of stress resistance, metabolism and ageing. ….



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 Posted: Thu Jan 28th, 2010 07:32

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One needs to be very careful in using animal models to help us understand the human immune system. Even the immune system of other mammals, such as mice, is significantly different from that of man (mice have a different number and function of TLR receptors, for example).

Even in higher primates there are differences in the innate immune system, such as transcription of Cathelicidin - which appears unique to man. For example - ponder SIV and HIV :)

The reliance upon animal models is one of the reasons that Biology has failed to produce solutions in the past few decades. Now that understanding of Genomes and transcription has overtaken that disability, there is an explosion of knowledge in-silico :)
 

Ute
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 Posted: Thu Jan 28th, 2010 07:52

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Excuse me, please,

I was inattentive - yes, I knew that animal models don't count any more....



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 Posted: Thu Jan 28th, 2010 08:54

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I didn't mean to be critical - my comment was just a reminder :)
 


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