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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...

tickbite
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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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tickbite
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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'.

Ruth Goold
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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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Prof Trevor Marshall
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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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