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Capnine - biofilm bacteria's dirty little secret
 Moderated by: Prof Trevor Marshall Page:  First Page Previous Page  1  2  3  4  5  6  7  Next Page Last Page  
 

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tickbite
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 Posted: Wed Jun 13th, 2007 17:59

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If they aren't thinking they can hurt us, then i'm assuming either pathologists know they're absolutely alien and playing some 'benign' role or a 'beneficial' role. Either of which I would like to still insite some kind of question as to what exactly they do. After all no organism in our bodies has a 'benign' role, other wise it wouldn't be there. Anyway, I guess the trick would be to find evidence of any such role instead of just a visual with no dynamic understanding. How about nanotechnology? Perhaps a tiny nano-syringe to extract nucleic acid. Anybody want to donate an electron microscope and some crazy nano technology tool making system? I've got the garage. We'll do it Bill Gates style.



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jrfoutin
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 Posted: Wed Jun 13th, 2007 21:33

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Gordon's ending comment on video was something to the effect of taking your bacteria to lunch or bringing them to the table because there are some things we use microbes break down to provide our energy.

The discussion on variety or not enough variety to establish phylo/heritance/relationship groupings (not just regrouping from scratch) is interesting and may have implications that good/bad bacteria might be a blurry line to draw, especially with regard to rather crude single and accute attack antibiotic use dominance in medicine. Made me think on the pulsed, long term combo abx effort of the MP and really appreciate enabling my immune system to figure out and handle what even antibiotic combos cannot.

Maybe a dumb question, but thinking about receptors and docking, if capnine, 25D and Benicar all arrive at the VDR at roughly the same moment in time, which would dominate and win the docking opportunity? If one is docked already in the VDR, would another displace? Paper, rock, scissors... single dominator effect or might 25D give capnine the competitive edge? Ki?

The required mechanism was that the bacteria needed to block the proper functioning of the VDR by producing a ligand which would displace 1,25-D from the VDR binding pocket. In turn, Olmesartan would displace the capnine, at least partially...

We can curtail 25D with food/light choices, capnine is stopped only by benicar... (at least partially) and ????



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Prof Trevor Marshall
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 Posted: Thu Jun 14th, 2007 00:10

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Maybe a dumb question, but thinking about receptors and docking, if capnine, 25D and Benicar all arrive at the VDR at roughly the same moment in time, which would dominate and win the docking opportunity?

Here is a graph from my Visiting Professor presentation to the FDA last year.



It depicts the concentration-dependent displacement of one ligand from a receptor by another. You might like to review my FDA presentation, or Google for "homologous binding" for for the details :)
 

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 Posted: Wed Jun 20th, 2007 05:21

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Trevor,

I was looking over a paper on capnine and have a question.

PMID: 2992489

I am not a chemist, so perhaps I am reading this the wrong way, but it seems that cysteine is necessary to form capnine, perhaps leading to lower cysteine and glutathione levels? Might that be why some people have positive effects from taking cysteine or glutathione, where in fact, they are helping the bacteria form more capnine?

Sincerely, Frans



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Prof Trevor Marshall
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 Posted: Wed Jun 20th, 2007 05:32

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No Frans, a single cysteine amino acid will make no difference when compare to the ton of them in your body. Even enough cysteines to block every VDR molecule will not be noticed. You have to be very careful drawing conclusions from science, many experienced investigators make the same mistake - not looking closely enough at phsyiological concentrations before drawing a conclusion.

And you can forget about glutathione. That substance is so far downstream from the cause of the disease it is 'in the noise'.

..Trevor..

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 Posted: Wed Jun 20th, 2007 05:42

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Trevor, I already was afraid I was wrong, maybe it is best to delete my post so as not to add to the noise.

Sincerely, Frans



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Ruth Goold
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 Posted: Wed Jun 20th, 2007 12:03

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Dr Trevor Marshall wrote: I have been alert to the close symbiosis between the retinoids and Vitamins D for some time. For example, either can function to hold together COMP, and both are active in Rhodopsin, but the retinoids have a relatively low Ki for the VDR.  

More support published today (admittedly from mouse work) for Trevor's ideas that retinoids are important in inflammation, even if they don't exert their influence through the VDR. The following article (published on-line in Science) indicates that (at least in mice) retinoids may influence inflammatory response through interactions with the cytokine TGF-beta.

Reciprocal Th-17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid

Daniel Mucida, Yunji Park, Gisen Kim, Olga Turovskaya, Iain Scott, Mitchell Kronenberg, Hilde Cheroutre 

Ruth



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Prof Trevor Marshall
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 Posted: Wed Jun 20th, 2007 13:51

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Ruth,
Those working with mice get side-tracked to NF-kappaB as the murine VDR doesn't even  transcribe the antimicrobial peptides, and operates totally different from that of man.

In Homo sapiens the key to the inflammatory response is not NF-kappaB, it is the type 1 nuclear receptors, pretty well all of them, interacting with 25-D, 1,25-D and the VDR.
 
NF-kappaB has a role, but just a role...
 

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 Posted: Wed Jun 20th, 2007 16:45

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Hmmm........ interesting.

The study below would seem to indicate that the promoter elements in rat and mouse AMP genes also contain binding sites for nuclear hormone receptors - do you think that a different NHR plays the role of the VDR in rodents?

Interestingly, NHRs were more prominent than immune cell-specific TFs in the analyzed AMPcg families [22 othologous families across rats, mice and humans].  Experimental evidence showed the involvement of NHRs in various immunomodulatory pathways. However little is known about their direct involvement in innate immunity.  Recently, there has been evidence that VDR plays a direct role in the induction of antimicrobial innate immune response. The results of the computational analysis which took a bird's eye view of the transcriptional regulators involved in multiple AMPcg families, concur with this evidence and revealed a number nuclear hormone receptor as candidates.  For example, GR, RXR-alpha, AR, VDR and T3R-alpha, seem to be involved in control of 20, 18, 17, 16 and 15 families respectively, out of 22 analyzed. I n addition we discovered 102 new motifs as candidate TFBS with a role in antimicrobial innate immunity.


From: Brahmachary et al.  Computational promoter analysis of mouse, rat and human antimicrobial peptide-coding genes.  Bioinformatics. 2006; 7(Suppl 5): S8

Obviously, the authors are a little behind the Marshall curve in their understanding of the role of NHR in transcritional control of AMPs in humans but their results also highlight some interesting differences between AMP TF binding sites in rodents and primates that will probably lead other researchers to recognize the species-specific aspect of transcriptional control.

Ruth



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Prof Trevor Marshall
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 Posted: Wed Jun 20th, 2007 18:38

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Ruth,
I am pretty busy at the moment, but I would be appreciative if you could spare the time to look over supplementary table 5 of Wang, et al, and make sure it correlates with the citation you posted:

Wang TT, Tavera-Mendoza LE, Laperriere D, Libby E, MacLeod NB, Nagai Y, Bourdeau V, Konstorum A, Lallemant B, Zhang R, Mader S, White JH. 2005. Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 19(11):2685-95 PMID 16002434

Yours is  a valuable citation for me, for some reason I had missed the Brahmachary paper.



The following research group failed to induce cathelicidin in the murine VDR:

Gombart AF, Borregaard N, Koeffler HP. 2005. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3.  FASEB J. 19(9):1067-77 PMID 15985530

Again, if you could take a quick look and let me know if there are any significant differences in the outlook of the two groups.

Ruth Goold
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 Posted: Wed Jun 20th, 2007 20:24

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Can do.  I'll get access to the papers at work tomorrow.
Ruth



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Janna
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 Posted: Sat Jun 23rd, 2007 15:30

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Wow! Congratulations, Dr. Marshall, and thanks for sharing the news!
 
I hope IDSA and ILADS quit arguing and take a look at what you are accomplishing.
 
Also, thank you for posting and answering what some members call “dumb” questions. I learn from both the questions and the answers.
 
[Kindly edit out if the following is irrelevant:]
 
Since I have neuroborreliosis, I checked if Borrelia is able to produce capnine (not that it needs to…just curious). According to Das et al, “ …the lipid biosynthesis pathway is absent from the spirochetes.” Source:  http://papers.gersteinlab.org/e-print/spirochete-jmmb/text.pdf.


 
Benk



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wrotek
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 Posted: Sat Jun 23rd, 2007 15:40

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Good eye. I remember Dr Marshall mentioned on 30th Lyme Anniversary video Presentation that borrelia lacks any lipid synthesis.



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 Posted: Sun Jun 24th, 2007 07:31

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To Wrotek:
 
Thanks. Obviously, not as good as your eye.   (I try not to miss any of your postings; they are particularly informative…and humbling: I don’t understand things as well as you do.)
 
Benk



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wrotek
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 Posted: Sun Jun 24th, 2007 07:59

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Oh :) I think If more we understand than more question we have.
For example I wonder if disease severity depends from bacterial ligand VDR affinity.



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Frans
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 Posted: Sun Jun 24th, 2007 11:43

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Trevor, I have a question regarding homologous binding etc.

I had an interesting discussion with a friend of an acqaintance, who turned out to work for a vitamin manufacturer.......

He was adamant that the last paper about vit. D being protective (which we have discussed in another thread) was game set and match.

I disagreed of course and after some heavy debating, we finally arrived where I wanted to be.

He understands that 25D etc. do NOT activate VDR.

However: he still believes that D has nowhere else to go but the VDR, after being hydroxylated to 1,25D.

To make a long discussion short, we ended at the following conclusion:

The main thing that decides if 25D displaces 1,25D from the receptor is the concentration in the cell itself. I got him wavering in his believes...

Now, I know this must be something that's incorporated in Ligplot, but I am just not sure.

Can you set me straight? How high will the cellular concentration be at which plasmaconcentration? Is there some ratio by which that happens ? It would be interesting to see what he can do with this information. (perhaps even without him being kicked out of his company :))

Sincerely, Frans

Last edited on Sun Jun 24th, 2007 11:45 by Frans



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jrfoutin
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 Posted: Sun Jun 24th, 2007 12:52

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Frans,
I guess we might expect broad economic repercussions when the real light dawns.

This realization may play a part of the overt or inadvertant denial process now and ahead.

Did your friend see the FDA visiting professor illustration above?--Janet



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 Posted: Sun Jun 24th, 2007 13:20

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Janet, I am not sure if that depicts the plasma concentration or the cellular concentration and how these two relate to each other.

Maybe there is a constant, that cellular concentration is always a certain percentage of plasmaconcentration or something like that?

I know from earlier posts that there is a definite difference in these two.

I know it is a detail, but it is an important one and I never would have thought I would need to go into such detail with anyone, this guy really knows something, but still, not enough   :D

Sincerely, Frans



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Frans
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 Posted: Mon Jun 25th, 2007 07:42

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Janet, Trevor,

I am looking over the presentation at the FDA again and see that cellular concentration is indeed in the graph.

I don't understand it yet, but will keep on looking at it till the quarter drops...

One thing I understand from the presentation is that the cellular concentration of Simvastatin and Telmisartan has been found in-vitro.

Has the same been done for 25D? Or is it simply a fact of the Ki value deciding how much of the drug will enter the cell?

Sincerely, Frans

PS  Janet, I think I will indeed have to show him this graph. Thanks for that !



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Prof Trevor Marshall
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 Posted: Mon Jun 25th, 2007 10:22

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Frans,
The concentrations at which the ligands will become active depends both on their affinity for the receptor, and on the concentrations and affinities of any competitors for the LBP (ligand binding pocket). That is what the graph depicts - competitive displacement of ligands.

The concentration of 1,25-D in the macrophage cytoplasm is about 2 nanomolar. We know that since its Kd (disassociation constant) is about 8.48 and also from a couple of in-vitro experiments.

However, 1,25-D has a Kd for the Glucocorticoid receptor of 8.12, for the Androgen receptor of 8.05 and for the alpha-Thyroid receptor of 8.41. There is little doubt it is also active in these receptors, as they form a subset of type 1 nuclear receptors which plays a key role in the immune system (see, for example, this paper).

And that info will boggle the mind of your vitamin-savvy associate...
 


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