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Video of Benicar activating the VDR
 Moderated by: Prof Trevor Marshall Page:  First Page Previous Page  1  2   
 

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inge
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 Posted: Fri Aug 15th, 2008 02:16

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Trevor,

I am afraid it does not really answer my question directly. If you are saying that there is no difference in the way olmesartan activates the VDR as compared to vitamin 1,25 once docked in to the LBP, how can olmesartan activate the VDR in a more controllable manner? (Come to think of it, maybe you said in earlier  posts that olmesartan activates many other receptors than the VDR in a more controllable manner? Then I am sorry for the confusion) 

Inge  



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 Posted: Tue Aug 19th, 2008 01:57

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Inge,
The FDA has a mantra "It's all a matter of Dose."
The agonist effect of Olmesartan occurs at higher doses, and the degree of effect can be adjusted by adjusting the dose.

Whereas with a drug which is too high an affinity, like Telmisartan as an antagonist, you cannot adjust the dose to modulate the degree of the effect.

So Olmesartan is able to displace 1,25-D, or capnine, from the VDR LBP in a controlled manner, dependent on Olmesartan dose (and the concentration of capnine or 1,25-D).
 
This is called "homologous displacement" in most pharmacology texts. It follows a characteristic S-shaped curve.
 

TikBitten
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 Posted: Mon Jan 26th, 2009 15:39

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Trevor-

MP Th1 patients endeavor to restrict VitD intake, sunlight exposure and chlorogenic acid so as to not interfere with the Olmesartan blockade.  Capnine, however, appears to be a compound that cannot be controlled.  So I am wondering...

1) Is there a diagnostic test to check the blood level of this lipid? 

2) Does the level of Capnine indicate the degree of biofilm/microbacterial load?

3) Would knowing the Capnine level predict potential interference with the Olmesartan blockade?

4) Assuming of course there's a lab that can perform the test in the first place, would this data help patients and physicians better understand IP progression and/or fluctuations?

Always interested to hear what you have to say on such matters...

Regards,

TB

Last edited on Mon Jan 26th, 2009 15:39 by TikBitten



____________________
Dx:Neurborreliosis 8/05|25D=46 1,25D=62 10/07|Avoid Sun&VitD since 10/07|Started Ph1&NoIRs 3/08|25D=18 3/08|25D=17 6/08|ModPh2 6/08|Ph2 9/08 stopped NoIRs|Ph3 1/09|25D=13 3/09|25D=10 5/09|25D=11 7/09|25D=15 9/09|25D=9 4/11
Prof Trevor Marshall
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 Posted: Mon Jan 26th, 2009 18:32

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Capnine is really just a "proof of concept." A substance from a common bacterium, Flavobacter, which has the ability to interfere with the immune system by blocking the VDR. I would be very surprised indeed if there was just one bacterial substance that had evolved to block the VDR. I certainly know that Caspase 3 attacks the VDR by proteolysis, and that substance is upregulated in infection. So there are many parallel pathways which all lead to the bacterial survival by closing down antimicrobial peptide production as much as possible.

Benicar displaces the ligands (it can't deal with the Caspase 3) in a concentration-dependent manner, like all receptor ligands.

More info in the discussion at
http://www.marshallprotocol.com/forum39/9348.html

The thing that is becoming really obvious right now is the sheer magnitude of the interactions between the 1 million (or so) bacterial genes and the 25,000 (or so) human genes. The potential total number of interactions is beyond quantification. That's why I say I would be surprised if only capnine was at issue in the pathogenesis, and I doubt that tests for any single metabolite would be much use.

I think it might be possible to use fluorescent markers to illuminate the "biofilm" matrix inside the cells, however, and we may be able to get that to a quantitative assay as the years go by. I spoke about this with respect to work being done on bacterial matrix as a byproduct of the prion research we heard at Karolinska in 2008.
The discussion and video about that is available (for members only) at
http://www.marshallprotocol.com/forum43/11932.html

I hope that helps,
Trevor

Lottis
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 Posted: Thu Jan 29th, 2009 04:18

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About activating the VDR;

This paper about bone reseach, has some bold conclusions;
http://tinyurl.com/ab2eal

The researchers concluded: "Activation of VDR by PUFAs and curcumin may elicit unique, 1,25(OH)(2)D-3-independent signaling pathways to orchestrate the bioeffects of these lipids in intestine, bone, skin/hair follicle, and other VDR-containing tissues." 

So, my concern is the curcumin. It is suggested that it is activating the VDR! It looks like we really need to handle curcumin with care.

Curcumin is sold over the counter as a painrelif, a powerful supplement for arthritis, and it is also a big part of curry powder (which I happen to love). http://www.phytochemicals.info/phytochemicals/curcumin.php

The MP tells us already, that it is immunomodulating, that we can use it in cooking only not as a supplement;

Tumeric "Twelve scientific, peer-reviewed publications since 1999 suggest that curcumin, the major yellow pigment in tumeric, curry and mustard, may potentiate apoptosis or inhibit growth of selected cancer cells or function as a COX-2 inhibitor several in-vitro and animal models." http://tinyurl.com/nflgz

Curcumin, Tumeric, Curry and Mustard
Some spices, which are produced from plants, can have a chemical effect upon the immune system. Significant use of curcumin or its derivatives, for example, should be avoided while on the MP.
This article (pdf) said, "Twelve scientific, peer-reviewed publications since 1999 suggest that curcumin, the major yellow pigment in tumeric, curry and mustard, may potentiate apoptosis or inhibit growth of selected cancer cells or function as a COX-2 inhibitor several in-vitro and animal models."

-While writing up the summary of my sarcoidosis history, I was reminded that my hip pain occurred in Japan and waned outside of Japan. I have therefore experimented a bit with the food I am eating in Japan. I am rarely eating out, but prepare all by myself. I used a curry spice almost everyday, which I have left out for the past 10 days and the hip pain is almost gone, and this after persisting for many months. On http://en.wikipedia.org/wiki/Curcumin I read about curcumin and its effects. ~Evelin


Does anybody else here have experience or comments about using this?

Last edited on Thu Jan 29th, 2009 09:01 by Lottis



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HTN,LVH,CHF,arrhythmia,variant angina,IBS?,fibromyalgia?salivarystones,gallstones,CPAP,|15feb-07 init. 1,25D 37,5,|25-D 7,8(15/2-07)| Ph1 30/5-08|Olmesartan alone|NoIR's|covered up|disabled|
wrotek
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 Posted: Thu Jan 29th, 2009 05:09

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Perhaps Dr Marshall could run it in-silico for VDR. This chemical looks very flexible. I wonder how high affinity is.

Lottis, the website requires registration to view article.

Ps i use curry for zucchini :| Actually i have an appetite for zucchini right now :)

Pubmed version, full article is here http://tinyurl.com/ab2eal
Vitamin D receptor: key roles in bone mineral pathophysiology, molecular mechanism of action, and novel nutritional ligands. Jurutka PW, Bartik L, Whitfield GK, Mathern DR, Barthel TK, Gurevich M, Hsieh JC, Kaczmarska M, Haussler CA, Haussler MR. Department of Integrated Natural Sciences, Arizona State University at the West Campus, Glendale, Arizona, USA. The vitamin D hormone, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], binds with high affinity to the nuclear vitamin D receptor (VDR), which recruits its retinoid X receptor (RXR) heterodimeric partner to recognize vitamin D responsive elements (VDREs) in target genes. 1,25(OH)(2)D(3) is known primarily as a regulator of calcium, but it also controls phosphate (re)absorption at the intestine and kidney. Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced in osteoblasts that, like PTH, lowers serum phosphate by inhibiting renal reabsorption through Npt2a/Npt2c. Real-time PCR and reporter gene transfection assays were used to probe VDR-mediated transcriptional control by 1,25(OH)(2)D(3). Reporter gene and mammalian two-hybrid transfections, plus competitive receptor binding assays, were used to discover novel VDR ligands. 1,25(OH)(2)D(3) induces FGF23 78-fold in osteoblasts, and because FGF23 in turn represses 1,25(OH)(2)D(3) synthesis, a reciprocal relationship is established, with FGF23 indirectly curtailing 1,25(OH)(2)D(3)-mediated intestinal absorption and counterbalancing renal reabsorption of phosphate, thereby reversing hyperphosphatemia and preventing ectopic calcification. Therefore, a 1,25(OH)(2)D(3)-FGF23 axis regulating phosphate is comparable in importance to the 1,25(OH)(2)D(3)-PTH axis that regulates calcium. 1,25(OH)(2)D(3) also elicits regulation of LRP5, Runx2, PHEX, TRPV6, and Npt2c, all anabolic toward bone, and RANKL, which is catabolic. Regulation of mouse RANKL by 1,25(OH)(2)D(3) supports a cloverleaf model, whereby VDR-RXR heterodimers bound to multiple VDREs are juxtapositioned through chromatin looping to form a supercomplex, potentially allowing simultaneous interactions with multiple co-modulators and chromatin remodeling enzymes. VDR also selectively binds certain omega3/omega6 polyunsaturated fatty acids (PUFAs) with low affinity, leading to transcriptionally active VDR-RXR complexes. Moreover, the turmeric-derived polyphenol, curcumin, activates transcription of a VDRE reporter construct in human colon cancer cells. Activation of VDR by PUFAs and curcumin may elicit unique, 1,25(OH)(2)D(3)-independent signaling pathways to orchestrate the bioeffects of these lipids in intestine, bone, skin/hair follicle, and other VDR-containing tissues. PMID: 18290715 [PubMed - indexed for MEDLINE]
From what i can see the work was in-vitro, to assess curcumin VDR binding.

Last edited on Thu Jan 29th, 2009 06:22 by wrotek



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Lottis
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 Posted: Thu Jan 29th, 2009 09:07

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Thank you, wrotek, I changed my link to your  http://tinyurl.com/ab2eal. :)

Yes, of course it is in vitro, but the good thing is that it is in human VDR.
I did not figure out if tumeric only activated the VDRe or the VDR, as the explanation for the immune modulating action.

Are you sure you are longing for zucchini? Maybe it is the curry powder you desire? ;)



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HTN,LVH,CHF,arrhythmia,variant angina,IBS?,fibromyalgia?salivarystones,gallstones,CPAP,|15feb-07 init. 1,25D 37,5,|25-D 7,8(15/2-07)| Ph1 30/5-08|Olmesartan alone|NoIR's|covered up|disabled|
wrotek
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 Posted: Sun Feb 1st, 2009 03:45

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Lottis, i think U may be right. I eat a lot of mustard :) I just hope curcumin won't happen to be an antagonist, after all.

Last edited on Sun Feb 1st, 2009 08:38 by wrotek



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IngeD
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 Posted: Wed Feb 4th, 2009 19:20

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Hi Lottis. You may want to experiment with the garlic. I have avoided it since early on in the MP as it immediately increased my IP. Guess it is because garlic is a natural antibiotic.

Interesting about the cummin/curry. Why is it all the stuff we love is potentially so bad? Maybe with all its antibiotic/anti inflammatory tendencies it was palliative for us by helping to turn off the immune system. Or just comfort foods.

Wrotek: interesting about the Japanese foods. Pre MP I had Japanese nearly daily. Love the Wasabi. That too is a natural antibiotic (pure horse raddish). Haven't touched any Japanese since start of MP mainly because it was the seafood I went crazy over :). Just realising HOW MUCH of the hot stuff I used to eat. Curry Laksa was another favourite. Avoided since start of MP as it usualy contains some kind of seafood but ...also very spicy.

So much to look forward to :). All the best. IngeD:cool:



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 Posted: Wed Feb 4th, 2009 19:30

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Remember that just because something is 'an antibiotic' doesn't mean it will kill the Th1 nasties. In fact, some of the strongest antibiotics, the beta-Lactams, actually encourage pathogens to change into the persistent form, and some, eg Rocephin, turn off the immune system's ability to go after the Th1 microbiota. Brian Fallon's studies showed that IV Rocephin is purely palliative.

Not all antibiotics kill all bugs...
 

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 Posted: Mon Feb 9th, 2009 09:03

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Dr Trevor Marshall wrote: ...Brian Fallon's studies showed that IV Rocephin is purely palliative.

Not all antibiotics kill all bugs...
 

At this point in time, do you feel Dr. Fallon fully recognizes that or might he still tend dispute certain aspects of it?

TB

Last edited on Mon Feb 9th, 2009 09:13 by TikBitten



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Dx:Neurborreliosis 8/05|25D=46 1,25D=62 10/07|Avoid Sun&VitD since 10/07|Started Ph1&NoIRs 3/08|25D=18 3/08|25D=17 6/08|ModPh2 6/08|Ph2 9/08 stopped NoIRs|Ph3 1/09|25D=13 3/09|25D=10 5/09|25D=11 7/09|25D=15 9/09|25D=9 4/11
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 Posted: Mon Feb 9th, 2009 09:21

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I haven't personally spoken to Brian since 2004, when I attended one of the very  few presentations of his study results.

I still have photos of some of the slides, and there is no equivocation in that presentation - nearly all symptomatic improvement from IV Rocephin had disappeared within 3 months of cessation of treatment. Further - a large number suffered significant  infection due to the IV catheter, etc (offhand, I can't recall if it was 25% or 33%)

Brian has weathered a firestorm from people who (anecdotally) believe otherwise, including ILADS LLMDs, and IMO this is why his NIH-funded Columbia study has not been published in a peer-reviewed journal.
 

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 Posted: Sat Feb 14th, 2009 08:21

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Dr Trevor Marshall wrote: John,
The docking trajectory is problemmatic right now, as the entire field of biology is working with a VDR model (PDB:1DB1) which is genetically engineered to have amino acids missing from a critical region (residues 164-216) of the VDR. The region through which the ligand most likely enters the VDR:X I can get around this later by "growing" the VDR using MD, but first I have to learn to crawl, then walk:):):)



Dr Marshall,

Is this still the situation of the engineerd VDR? That quote is a litte old. And is this a human VDR?

My next question is answered before somewhere but I do not remember where;

Which of the ARBs and Statins have you found out to be agonist of the VDR?:?

Last edited on Sat Feb 14th, 2009 08:22 by Lottis



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HTN,LVH,CHF,arrhythmia,variant angina,IBS?,fibromyalgia?salivarystones,gallstones,CPAP,|15feb-07 init. 1,25D 37,5,|25-D 7,8(15/2-07)| Ph1 30/5-08|Olmesartan alone|NoIR's|covered up|disabled|
Prof Trevor Marshall
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 Posted: Sat Feb 14th, 2009 10:09

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Please move the off-topic discussion about Food allergies (etc) over to:

General Questions and Discussion


There are a lot of people who watch my Perspectives forum very closely for news of new science, and this is not a good place to discuss general stuff. I will try to move the comments that were posted while I was up at the Stanford conference (these last few days) to that correct forum.

Please continue the conversation at:

http://marshallprotocol.com/view_topic.php?id=13131&forum_id=11

I have transferred the posts over there to that general forum.

I messed up the transfer and lost some posts, sorry about that. I have no idea what happened. Please accept my apology if some of your contributions were accidentally deleted.

(Please send me a PM if you have copies of any of the missing material , I will add them to the header.)

 
 

Last edited on Sat Feb 14th, 2009 10:39 by Prof Trevor Marshall

Prof Trevor Marshall
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 Posted: Sat Feb 14th, 2009 13:40

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Is this still the situation of the engineered VDR? That quote is a litte old. And is this a human VDR?
My next question is answered before somewhere but I do not remember where;
Which of the ARBs and Statins have you found out to be agonist of the VDR?


Lottis,
Yes, the VDR in the PDB Crystal structures are engineered like PDB:1DB1, even the Rat VDR (PDB:1RK3). I can extend them with the new version of Modeller, I think. But it will take a quite a lot of work. Maybe a PhD student will be available to help me one day :)

Only Olmesatan is definitely a VDR agonist. I have some suspicion about Simvastatin being a very, very weak one. But that's all I have found :)
 

Prof Trevor Marshall
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 Posted: Sat Feb 14th, 2009 13:42

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At this point in time, do you feel Dr. Fallon fully recognizes that or might he still tend dispute certain aspects of it?

When I spoke with him in 2004 he was definitely aware that Rocephin was not acting as an antibiotic in his trial cohort :)
 


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