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baypilot
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Posted: Wed Jul 1st, 2009 15:28 |
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WHAT İS THE MEANİNG OF PXR PLEASE
THANK U....
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-Sarcoidosis/lymph nodes mediastine/shortness of breath stageI(DEC06)
-phase1 Olmetec40mg/6h(Apr08.2010), mino 25mg (Apr.23)
-Initial 1,25D50 25D23(nov08)
-second.125d38 25D8(nov09)
-Latest25D (Apr.2010)9.8
-NoIRs covered up Low lux home exp work u
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Hogan
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Posted: Wed Jul 1st, 2009 15:44 |
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hope this helps
A new paper is out on the PXR - a detailed in-vitro study of agonists.
Download the PDF from http://www.biomedcentral.com/content/pdf/1471-2148-8-103.pdf
or browse the main text at http://www.biomedcentral.com/1471-2148/8/103
Of note is confirmation of Hyperforin (St John's Wort) and new ones (to me) like TCDD (Dioxin).
I note that this paper saves me the bother of checking out Lithocholic acid, which is now confirmed as a PXR target. There are many Pubmed papers saying that the VDR is a target for Lithocholic Acid, but I have previously said that my modelling does not show that, and I suspected it was an error introduced by these wet-biology studies not contemplating the existence of PXR, or its key role in the VDR metabolism.
Although many steroid agonists were identified, it is unclear to me whether they would exist in-vivo at the concentrations identified in this study.
Of interest is that they found that 1,25-D and 25-D were not agonists. Since my in-silico work has identified the very high affinity they have for the PXR, it follows that they must be antagonists, which is what I had deduced and published in our recent paper "VDR discovery outpaces .. etc" (figs 1,2 of my paper).
Anyway - I have printed out this article and will read it in my spare time over the next few days... Let me know if you find anything significant...
Interesting...
"PXR detects potentially harmful xenobiotics and induces genes that flush the offending chemicals from the body (3–5). An undesirable side effect of this xenobiotic detoxification system is that drugs that activate PXR can stimulate the metabolism of other drugs, sometimes with life-threatening consequences."
In chronically ill patients, people who are really ill, antibiotics alone will not kill the persistent pathogens. If you get the disease early enough, then the patients will respond to the antibiotic reasonably well. But as the bacteria slowly overcome the patients immune system and shut down the patient’s own immune response, you get down to the point where the antibiotics just do not work anymore in vivoA type of scientific study that analyzes an organism in its natural living environment..
Remember that most antibiotics are actually tested outside the body, in the lab. When they are operating inside the body it’s a totally different environment. All three major antibiotics that we use, well actually minocyclineBacteriostatic antibiotic used by Marshall Protocol patients. and clindamycinBacteriostatic antibiotic used by patients on the Marshall Protocol. and an antibiotic targeted against Tuberculosis: rifampin, they’re all part of the VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response.-metabolism graph that I showed you earlier on today as they are agonists for the PXR. They behave differently in vivoA type of scientific study that analyzes an organism in its natural living environment..
Two things are disabling the innate immune system. One is the bacteria themselves. The bacteria are in a number of different ways overcoming the innate immune system and slowly shutting it down, thus allowing the bacteria to persist within the phagocytes. And then the other thing is exogenous Vitamin D. Because all we’re doing when we give Vitamin D supplements to a patient is actually making it easier for the bacteria to shut down the innate immune system.
"I’ve wondered if my immune system is awakening faster than .. my liver .. can detox"
Yes, it's possible. I am generally more happy when people maintain their mino at the 100mg level, as that is what the early adopters all did. The 25mg step came in later, after 2004. Since mino is a PXR agonist it may well have benefits at 100mg, benefits that the cohort currently is not experiencing. I just don't know...
Minocycline is a strong PXR agonist. It increases transcription of CYP3A4 (which breaks down 1,25-D). It increases CYP27A1 expression too (look at my Figure 1 of the Bioessay).
"A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine"
http://www.ncbi.nlm.nih.gov/pubmed/18505790
Clindamycin was also reported to be a PXR agonist, but I was unable to confirm that in-silico. I did confirm minocycline. I suspect that their in-vitro observation was being confused by Clindamycin acting on one of the other orphan nuclear receptors. We know so little about them at this point...
So, is the phosphorylation angle important? Probably not, IMO. the VDR seems to be where it all comes together...
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paulalbert
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Posted: Wed Jul 1st, 2009 20:23 |
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It's a nuclear receptor. When activated by minocycline or Benicar, it transcribes CYP3A4, an enzyme which breaks down 1,25-D into 25-D.
For a list of other MP terms, check out the Knowledge Base glossary.
http://mpkb.mp-dev.com/doku.php/home:patients:glossary
Paul
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