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The Anti-Microbial Peptides
 Moderated by: Prof Trevor Marshall Page:  First Page Previous Page  1  2  3  4  Next Page Last Page  
 

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tickbite
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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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wrotek
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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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tickbite
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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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wrotek
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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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tickbite
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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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MarkN
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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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tickbite
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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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Prof Trevor Marshall
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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

tickbite
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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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Prof Trevor Marshall
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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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wrotek
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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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 Posted: Fri Apr 27th, 2007 15:53

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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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wrotek
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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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 Posted: Fri Apr 27th, 2007 17:54

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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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 Posted: Sat Apr 28th, 2007 06:20

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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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