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Dr Trevor Marshall
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Posted: Fri Dec 7th, 2007 10:19 |
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You folk want answers sooner, rather than later, so the infrastructure built by SETI would be a hindrance, rather than a help.
Look at http://www.Gromacs.org
That is the molecular dynamics software, it is open source.
..Trevor..
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wrotek
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Posted: Fri Dec 7th, 2007 10:44 |
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Thank You Dr Marshall i will do some reading.
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wrotek
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Posted: Tue Dec 11th, 2007 04:57 |
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I don't know how important it is, but cafestol has been identified as a agonist for nuclear receptors, Farnesoid and Pregnane X Receptors (FXR and PXR)
http://mend.endojournals.org/cgi/content/abstract/me.2007-0133v1
(PMID: 17456796 [PubMed - indexed for MEDLINE])
I know also that relations between nuclear receptors exist, and are very complex .
Also Cafestol, a diterpene present in unfiltered coffee brews such as Scandinavian boiled, Turkish and Cafetière coffee, is the most potent cholesterol-elevating compound known in the human diet.
It is i think very important to notice, that cafestol and kahweol are exclusively present only in coffee, no where else, which cannot be said about chlorogenic acid.
http://ntp.niehs.nih.gov/ntp/htdocs/Chem_Background/ExSumPdf/Cafestol.pdf
Cafestol and kahweol, which are naturally occurring diterpenes found only in coffee,
I have also noticed that FXR, PXR, VDR are all a bile sensors.
http://www.kumc.edu/pharmacology/Pei-zhen_Song.html The bile acid sensors that have been identified include FXR, PXR, and VDR. FXR is the major bile acid sensor.
It is just a common sense, but i think that messing additionally with nuclear receptors cannot be a good thing 
Last edited on Tue Dec 11th, 2007 07:06 by wrotek
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Dr Trevor Marshall
Research Team
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Posted: Tue Dec 11th, 2007 08:22 |
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The Pregnane X Receptor, PXR, is in the same sub-family as VDR and is key to balance of the D metabolism. Our new paper, which I will be able to put on the web at Christmas, goes into its role in some detail.
PXR is a receptor which is believed activated by quite a number of molecules, including Rifampin, the primary antibiotic used in Tuberculosis therapy.
PXR downregulates CYP24A1, the enzyme that breaks down 1,25-D into inactive 24,25 and 25,26 metabolites after the VDR has done its job. It is also responsible for transcribing the CYP27A1 enzyme that changes Vitamin D to 25-hydroxyvitamin-D.
25-D and 1,25-D both block the actions of PXR, regulating the enzymes to maintain balance. All this is shown in Figure 1 and Figure 2 of the new paper.
So any chemical which activates or deactivates the PXR directly affects the D metabolism, and the transcription of thousands of genes.
Thanks for the tip, Wrotek. I will look more closely at cafestol...
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wrotek
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Posted: Tue Dec 11th, 2007 09:00 |
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http://en.wikipedia.org/wiki/Cafestol
coffee is 0,6% cafestol by weight.
I have measured my cup of coffee and it weights 9,300mg. It means that in one cup of coffee there is 55,8mg of cafestol.
I wonder how strong affinity of this ligand is and how strong it's actions.
Dr Marshall i have found Your post in this topic http://tinyurl.com/2a7wqw about cyp24a1
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Ruth,
The mechanism is simpler than that.
I have just written a review paper (which will hit print later this year) which explains it all in some detail, but briefly, if you were a persistent intracellular bacterium it would make sense for you to want to evade the immune system. Imagine your surprise when you found you could knock out both the Cathelicidin and beta-Defensin anti-microbial defenses by blocking the operation of just one receptor, the VDR!
When you block the VDR you interrupt the down-regulation of the production of 1,25-D (via the CYP27B1 and [highlight= rgb(255, 255, 136);]CYP24A1 metabolisms), and therefore the level of 1,25-D rises to dangerously high levels. This in turn depresses the transcription of CYP27A1 by the PXR receptor, lowering the level of generated 25-D, but that doesn't worry you either (the bug).
However, the high level of 1,25-D also interrupts the PXR receptor transcribing a number of Xenobiotic enzymes (detoxifying enzymes)(pXr) as well as CYP27A1. This is not good for the safety of your host. The high 1,25-D levels also stop the Thyroid and Glucocortiocid receptors from working properly, as well as GPCRs in, for example, the retina (Rhodopsin). But again, this doesn't affect the bacterium, only the host. The trick is to make sure the host just stays pretty sick, but doesn't die...
It would be a neat plan of action, don't you think? The only problem might arise if a VDR agonist happened on the scene, capable of displacing your ligand from the VDR, making the VDR work properly again, and restart transcription the genes producing those nasty anti-microbial thingys...
..Trevor..
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very complex and difficult 
Last edited on Tue Dec 11th, 2007 09:07 by wrotek
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Dr Trevor Marshall
Research Team
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Posted: Tue Dec 11th, 2007 09:10 |
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very complex and difficult
No, very interesting and exciting
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wrotek
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Posted: Tue Dec 11th, 2007 09:25 |
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So we have a chlorogenic acid which decreases competence of VDR by binding to it antagonistically, and cafestol which increases 1,25-D. Both reactions we try to reverse with MP, i think ?
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wrotek
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Posted: Thu Jan 10th, 2008 17:39 |
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Perhaps this can be an interesting lecture.
Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative
http://www.jlr.org/cgi/content/full/46/1/46#FIG2 http://www.biochem.wisc.edu/courses/biochem911/materials/readings/Adachi.pdf
(first link stopped working somehow)
And other fresh 2008 study http://tinyurl.com/2h74kh
Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia.
Ishizawa M, Matsunawa M, Adachi R, Uno S, Ikeda K, Masuno H, Shimizu M, Iwasaki KI, Yamada S, Makishima M.
1alpha,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a vitamin D receptor (VDR) ligand, regulates calcium homeostasis and also exhibits noncalcemic actions on immunity and cell differentiation. In addition to disorders of bone and calcium metabolism, VDR ligands are potential therapeutic agents in the treatment of immune disorders, microbial infections, and malignancies. Hypercalcemia, the major adverse effect of vitamin D(3) derivatives, limits their clinical application. The secondary bile acid lithocholic acid (LCA) is an additional physiological ligand for VDR, and its synthetic derivative, LCA acetate, is a potent VDR agonist. In this study, we found an additional derivative, LCA propionate, is a more selective VDR activator than LCA acetate. LCA acetate and LCA propionate induced expression of the calcium channel transient receptor potential vanilloid type 6 (TRPV6) as effectively as that of CYP24A1, while 1,25(OH)(2)D(3) was more effective on TRPV6 than on CYP24A1 in intestinal cells. In vivo experiments showed that LCA acetate and LCA propionate effectively induced tissue VDR activation without causing hypercalcemia. These bile acid derivatives have the ability to function as selective VDR modulators.
PMID: 18180267 [PubMed - as supplied by publisher]
Detection of lithocholic acid in multiple sclerosis brain tissue
http://www.springerlink.com/content/q145g045j1712g51/
Lithocholic acid can carry out in vivo functions
of vitamin D
http://www.pnas.org/cgi/reprint/0703512104v1.pdf?ck=nck
LCA is poorly absorbed so it is likely that 10 g per day is absorbed. From these calculations, it would appear that LCA has in vivo activity of 1/1,000 that of 1,25-(OH)2D3
Last edited on Thu Jan 10th, 2008 18:29 by wrotek
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jcwat101
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Posted: Fri Jan 11th, 2008 00:09 |
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The role of the bile acids acting on the VDR is why I believe my immunopathology increases during the period following a meal with fat in it (peak effect is 50-90 minutes after the meal). I wonder if that is part of the reason why I used to think I felt better when I ate a low fat diet. I would not expect everyone to react this way, as there might be differences in levels of VDR blockage/activation.
I have mentioned this effect in my PR: Joyce Waterhouse's Progress Report
Joyce Waterhouse
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20 yrs with CFS/FM/Lyme/IBS, food sensitivities; 1,25D/25D 8/04:64/11 1/05:22/6 9/05:1,25D=12 10/06:22/8, 4/07:25/<4 chewed Ben. 40mg q8h; Mod. P2: 2/23/05, P2: 4/06; P3: 1/1/07
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wrotek
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Posted: Fri Jan 11th, 2008 10:03 |
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I thought only 1,25-d can activate VDR.
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Dr Trevor Marshall
Research Team
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Posted: Fri Jan 11th, 2008 11:05 |
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Lithocholic acid seems too large and too inflexible to agonize the VDR. On the other hand, it could well be a ligand for VDR's sister, the PXR (Pregnane Xenobiotic Receptor) which has a more promiscuous binding pocket.
Wet biologists would probably not be able to notice the difference, especially if they were following the methodology outlined in the paper Joyce cites. In other words, I think they made a mistake saying that Lithocholic acid is a VDR agonist. It may well affect gene expression via PXR or some unknown secondary mechanism, but I would want to see it dock into the VDR before declaring it a VDR agonist.
Figure 1 of my soon-to-be-on-the-streets new paper goes into the role of PXR in more detail.
I am at a conference this weekend, so I can't do any checking beyond what I have already done - the conclusion of which was that the study cited by Joyce drew its conclusions in error.
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NickBowler
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Posted: Fri Jan 11th, 2008 12:26 |
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I have been reading about a new patented supplement called AC-11 on the market that has in contrast to many, been through some controlled research studies. It is touted to improve DNA repair by around 10%, increase apoptosis in a cancer cell line (HL-60) massively, increase lymphocyte production around 8%, and reduce lipopolysaccharide induced TNFalpha production by between 65-85%. The LD50 is greater than 8g/Kg so it is very non-toxic.
Could we be looking at a VDR agonist here? The proposed ligand would be a building block of the aqueous extract from Cats Claw called quinovic acid:
http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/2004/6/i18/abs/ol048787b.html
http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=1367339&dopt=AbstractPlus
By the way even if it does not activate the VDR does activation of the VDR by 1,25D or Benicar improve DNA repair processes? - if so I presume that would not include mitochondrial DNA?
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Dr Trevor Marshall
Research Team
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Posted: Sat Jan 12th, 2008 09:46 |
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NickBowler,
It is absolutely essential than someone on the MP not take any supplements or medications without first checking with the moderators. In the unlikely event that the supplement actually does what is advertised, and your body's immune system is restored in some way, the results could kill you.
IMO, this is what happened in the TeGenero study.
For the last couple of days I have been getting my mind around DNA repair, and other advanced genomic topics, at a conference at the Salk Institute led by two Nobel laureates in the field of genomics. Please do not believe anything you read about cat's claw, or any other sort of claw, as correct and definitive. There are very few people in the world that have the capability of truly grappling with that topic...
As for believing something because it is published in a peer-reviewed journal, well, you are all still ill, despite decades of papers being published about your condition. Do you really believe that any of those authors really knew what they were doing? Or their peer-reviewers?
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wrotek
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Posted: Sat Jan 12th, 2008 11:25 |
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Dr Marshall, is this like molecule has to have broken 4 steroid ring structure, so it could change alignment inside LBP, to switch the VDR on ? I understand that rigid 4 steroid ring structures can anter LBP but are not enough flexible to do their job, so i wonder if 1,25-D has to take similar to 4 ring tight shape before entering LBP.
Can we somehow see entrance of the receptor and inside of the walls of VDR LBP ?
I would be nice to see total video of 1,25-D entering the receptor and aligning inside.
When i look at conformation of 1,25-D inside receptor, i see that it is "stretched" through this one broken steroid ring.
Photograph taken from http://www.rcsb.org/pdb/explore.do?structureId=1DB1
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NickBowler
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Posted: Sat Jan 12th, 2008 11:52 |
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O no, you misunderstand me, I have no intention of volunteering myself as a guinea pig with this new supplement, I am just fascinated by the whole unfolding science. If this product does have vdr activity then it ought to be pointed out to the manufacturer what the implications might be as it may have potential (when properly studied of course). And the whole concept of possible DNA repair in relation to the VDR modulation is a whole new dimension to the science that you are pioneering is it not?
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Claudia
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Posted: Sat Jan 12th, 2008 13:32 |
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Earlier you said that CA is "cumulative" so I am wondering how long it takes to get it out of our system? I absolutely love coffee and for years I have known it is bad for me. The first time I was told to stay away from coffee it was by a chiropractor/natural health practitioner back around 1980. She said, "It will interfere with your immune system." Too right. If I have just one cup, I feel wonderful and am bouncing off the walls for at least 12 hours (which means if I have coffee with dinner, I'm charging around the house untill 4am - LOL). I try to limit this sort of personal excess (to anyone else it would be a trifle) to once a week and probably shouldn't do it at all.
Anyway, the question is, I know the caffein wears off in a matter of hours, but is the chlorogenic acid staying active a similar amount of time? OR lingering for days or whatever? I'm trying to figure out if my effect is mostly the caffein, which is bad enough, or if I'm getting IP relief from the CA, which of course would be worse.
Thanks ~ Claudia
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MP Phase1 23Mar_06; Phase2 July 10_06; Phase3 Nov 4_06. Dx Thyroiditis (Thyroxine); arthritis; glaucoma; CFS (1988-92);Kidney & bladder probs. Feb06 1,25D=43.3; Aug07 1,25D=27.5; Feb06 25D=44; Aug07 25D=28; Nov07 25D=36; Mar08 25D=16.4
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wrotek
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Posted: Wed Jan 16th, 2008 18:35 |
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What about hyperforin http://www.ncbi.nlm.nih.gov/pubmed/10852961
St. John's wort (Hypericum perforatum) is an herbal remedy used widely for the treatment of depression. Recent clinical studies demonstrate that hypericum extracts increase the metabolism of various drugs, including combined oral contraceptives, cyclosporin, and indinavir. In this report, we show that hyperforin, a constituent of St. John's wort with antidepressant activity, is a potent ligand (K(i) = 27 nM) for the pregnane X receptor, an orphan nuclear receptor that regulates expression of the cytochrome P450 (CYP) 3A4 monooxygenase. Treatment of primary human hepatocytes with hypericum extracts or hyperforin results in a marked induction of CYP3A4 expression. Because CYP3A4 is involved in the oxidative metabolism of >50% of all drugs, our findings provide a molecular mechanism for the interaction of St. John's wort with drugs and suggest that hypericum extracts are likely to interact with many more drugs than previously had been realized. PMID: 10852961 [PubMed - indexed for MEDLINE] So hyperforin acts in the same way on the same receptor - PXR - as cafestol does. So if Hypericum Perforatum is a natural 'remedy' or rather masqerader of a depression, is not coffee then too ?
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Dr Trevor Marshall
Research Team
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Posted: Wed Jan 16th, 2008 22:23 |
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Good find, Wrotek, thanks. So it hits the PXR...
I never could handle St John's Wort, and I guess this is why
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wrotek
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Posted: Wed Jan 16th, 2008 22:42 |
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That is nice to hear When i was looking at wikipedia's PXR description, there was a link to CYP3A4 gene. I followed it and found enormous table in the end of the page http://en.wikipedia.org/wiki/CYP3A4
It is divided into 3 sections : Substrates, Inhibitors and Inducers of CYP3A4 .
Inducers section contains among others rifampicin, dexamethasone, hyperforin.
Perhaps it is worth looking since it is pretty large.
Quercetin is said to be a strong inhibitor of CYP3A4 (i don't know if inhibition of CYP3A4 is the same as inhibition of PXR every time) for example
Bergamottin (constituent of grapefruit juice) is also on the inhibitors list, maybe that is why people use it in grape fruit seeds extracts.
Last edited on Wed Jan 16th, 2008 22:53 by wrotek
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wrotek
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Posted: Sat Jan 19th, 2008 22:39 |
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Stay tuned to PXR: an orphan actor that may not be D-structive only to bone
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=539210
Pregnane X receptor (PXR) plays an important role in detoxifying xenobiotics and drugs. In this issue of the JCI, Pascussi et al. provide convincing evidence that PXR can also induce vitamin D deficiency and bone disease because of its ability to cross-talk with the vitamin D–responsive gene that catabolizes 25-hydroxy-vitamin D and 1,25-dihydroxyvitamin D. This cross-talk behavior has important health ramifications and can be mitigated through the identification and treatment of PXR-induced vitamin D deficiency. Since these initial observations were made, there have been a multitude of reports of abnormalities in calcium, vitamin D, and bone metabolism in subjects chronically treated not only with antiepileptic drugs but also with glucocorticoids, rifampin, and antiretroviral drugs (3–6). The disturbances observed in antiepileptic drug–treated patients were noted to be very similar to those of patients with vitamin D deficiency. More than 50% of children and adults receiving chronic antiepileptic drug therapy are at risk for developing abnormalities in calcium, vitamin D, and bone meta-bolism (3). However, cardiac patients who had been treated with conventional doses of phenytoin for control of arrhythmias were found to be free of these abnormalities (7).Antiepileptic drug–induced alterations in calcium and bone metabolism can include biochemical abnormalities such as hypocalcemia, hypophosphatemia, and elevated serum concentrations of alkaline phosphatase, parathyroid hormone, and 1,25-dihydroxyvitamin D [1,25(OH)2D]. The biochemical hallmark for this disorder is reduced serum concentration of 25-hydroxyvitamin D [25(OH)D], the major circulating form, which is a barometer for a person’s vitamin D status Hahn et al. (6) noted that rats that initially received phenobarbital had increased blood levels not only of 25(OH)D but also of 24, 25-dihydroxyvitamin D3 [24,25(OH)2D3], while the 1,25(OH)2D3 levels were unchanged. However, after 21 days of treatment, both 25(OH)D3 and 24,25(OH)2D3 concentrations and intestinal calcium absorption were significantly decreased, while 1,25(OH)2D3 concentrations increased by 80%.
interesting...
Last edited on Sat Jan 19th, 2008 23:01 by wrotek
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