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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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Frans
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 Posted: Sat Apr 28th, 2007 06:37

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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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Prof Trevor Marshall
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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.

wrotek
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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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Russ
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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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Prof Trevor Marshall
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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.

tickbite
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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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Prof Trevor Marshall
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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:)

Russ
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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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Prof Trevor Marshall
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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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 Posted: Thu Dec 6th, 2007 05:10

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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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Prof Trevor Marshall
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 Posted: Thu Dec 6th, 2007 05:30

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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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 Posted: Thu Dec 6th, 2007 05:53

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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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Jimbbb
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 Posted: Fri Dec 7th, 2007 07:42

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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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Frans
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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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wrotek
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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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Prof Trevor Marshall
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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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