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Posted: Tue Mar 29th, 2005 00:48 |
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Vitamin D--also known as calciferol--has several forms or metabolites. Vitamin D was misnamed when it was discovered in 1922. It is not a true vitamin because an ongoing nutrient source is not required to sustain normal levels in the body. Rather, it is autonomously synthesized in the cells of the skin into the biologocally active form in reaction to sunlight or bright lights.
History of Vitamin D
In 1925, Adoph Windaus isolated three forms of the vitamin: two derived from irradiated plant sterols, which he called D1 and D2, and one derived from irradiated skin, which he called D3.
In 1931, the chemical makeup of D2 (ergocalciferol) which is derived from the precursor molecule ergosterol, was defined.
In 1936, Windaus synthesized the molecule 7-dehydrocholesterol and, then converted it by irradiation to vitamin D3, now known as cholecalciferol.
Although it was assumed that vitamin D was photosynthesized in the skin from 7-dehydrocholesterol, the final proof did not emerge until more than three decades later.
In 1968 an active substance identified as 25-hydroxyvitamin D3, was isolated and later proved to be produced in the liver. During the next two years, the existence of a second active metabolite was discovered and found to be produced in the kidney.
In 1971, the chemical/molecular structure of this metabolite, was identified as 1,25-dihydroxyvitamin D3. It was now clear that the liver changes vitamin D3 to 25-hydroxyvitamin D3, the major circulating form of the vitamin. The kidneys then convert 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3, the active form of the vitamin.
1,25-dihydroxyvitamin D3, the active form of vitamin D, was reclassified as a hormone that controlled calcium metabolism. A hormone is a chemical substance produced by one organ and then transported in the bloodstream to a target organ, where it causes a specific biological action.
Dr Tony Norman, at UCR, discovered 1,25-D and has spent his life studying it, and other related compounds like 24,25-D. Here is his bio:
http://biochemistry.ucr.edu/faculty/norman.html
Calciferol--also known as calcidiol or 25-hydroxycholecalciferol or 25-hydroxyvitamin-D or simply 25-D--is an inert, biologically inactive precursor of hormone D. It is produced in the liver from Vit D2 and Vit D3 and is the major circulating form of Vitamin D. It is the substance that is used to produce the hormone (in the kidneys) which is the biologically active form.
Persons with Th1 inflammation get most of their 25-D from ingested sources. Naturally occurring dietary sources of Vitamin D2 and D3 (especially fish, fish oils, liver, eggs), foods supplemented with Vitamin D (dairy products, cereals, processed foods) and vitamin supplements are the body's main source of calciferol (25-D).
A small amount of 25-D may be generated by exposure to sunlight. Sunlight catalyzes the production of the Vitamins D from 7-dehydro-cholesterol in the skin. In healthy folks a significant amount of 25-D will be generated, but in folks with Th1 disease that will energetically be converted to 1,25-D by the disease process, and 1,25-D is thus the resulting primary product. In healthy folks there will be remanent 25-D generated.
Some plants and fungi convert ergosterol (a plant sterol) into Vitamin D2 (ergocalciferol) in response to light and these plants can then be a minor nutritional source of calciferol for humans.
Taking Vitamin D supplements/fish oils or eating foods high in Vitamin D will increase the level of 25-D.
Calciferol (25-D) is measured in nanograms/milliliter. The metric measurement is nmol/L. Some labs measure both Vitamin D2 and D3 and then provide a total 25-D level.
"Unfortunately, one cannot rely on nutritionists to understand the actions of Cholecalciferol. They still call it a Vitamin. It is not, it is a steroid hormone precursor. All the evidence I am seeing indicates our body doesn't need it at all. All in all, the misclassification of Cholecalciferol (as a Vitamin) is likely to become one of the biggest debacles clinical science has ever made."
Dr. Trevor Marshall, PhD
Calcitriol--the active metabolite--is also known as 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin-D3 or simply 1,25-D. It is the most potent secosteroid hormone in the human body and affects almost every cellular activity.
http://tinyurl.com/7hbz5
1,25-D is formed in the kidneys, the kerotinocytes of the skin and many other tissues of the body. The level of production is normally tightly controlled in healthy people. It is measured in picograms (which is 1/1,000,000,000,000 of a gram) per milliliter. The metric measurement is pmol/L.
1,25-D is directly synthesized from 7-dehydrocholesterol when sunlight falls on the keratinocytes of the skin. Because the keratinocytes of Th1 patients are parasitized by CWD bacteria, they produce interferon-gamma (which is part of the bacterial defense mechanism) and TNF-alpha. These cytokines cause the cells of Th1 patients to produce much more 1,25-D in their skin than healthy folks. In patients with Th1 inflammation, the production, by sunlight, of 1,25-D in the skin predominates the production of 25-D. Studies show that all 25-D produced in the skin from sunlight is hydroxylated directly into 1,25-D, leaving no 25-D to be stored.
Since biochemists have been doing their homework, it makes clinical science look all the more clumsy:
http://biochemistry.ucr.edu/faculty/norman.html
There is no dietary requirement for calciferol(25-D) to produce 1,25-D. As long as humans have access to minimal sunlight several months of the year,they will not become deficient in this active metabolite (1,25-D). Ten to 15 minutes of natural sunlight or daylight exposure to only the forearm or face twice a week (for example, while driving) supplies all the active metabolite of Vitamin D (1,25-D) necessary for health.
Nutritional sources (natural and supplemented) provide the precursor, 25-D, which is stored for later use and has a half life of 2-6 months, as a safeguard for later use. When sunlight exposure is not available the body uses its stored calciferol to produce the biologically active form of Vitamin D in other tissues of the body. Patients with Th1 disease generate their 1,25-D requirements from much lower levels of light than healthy people, and rarely need any nutritional 25-D.
1,25-D is generated in the macrophages when Th1 cytokines mRNA is released by phisphorylation of the protein dimer Nuclear Factor Kappa B by the I-kappaB kinase polymorphs.
The mitochondria of the activated macrophages are responsible for producing 1,25-D in the cytoplasm of the infected cells. There is only one of the D-metabolite-converting-enzymes present in the mitochondria, the enzyme which converts 25-D into 1,25-D. Interferon-gamma (released by the Th1 bacteria) energetically catalyses this conversion by as much as 30-fold. So the more 25-D that is available to the inflammed tissue, the more 1,25-D will be generated. Ingestion of Vitamin D, from food an supplements, causes 25-D to be available to fuel the conversion to 1,25-D in the mitochondria of the cytoplasm of activated (infected) macrophages under the influence of Interferon-gamma.
Light falling in the eyes fuels inflammation in the eye and may cause generation of 1,25-D.
When cell wall deficient bacteria invade the macrophages of the immune system, calcitriol is produced (due to the Th1 immune system response) causing the level of calcitriol to exceed the upper limit normally controlled by the kidneys. As a result, the level of calciferol (25-D) may be reduced because it is being rapidly converted into calcitriol (1,25-D).
It is essential to measure both calciferol (25-D) and calcitriol (1,25-D) to determine if there is a Vitamin D deficiency. The level of the inert precursor (25-D) does not always directly reflect the level of the active metabolite (1,25-D). In persons with Th1 inflammation (often undiagnosed) the level of measured calciferol (25-D) may be low (due to rapid use of this precursor) while the level of the active metabolite, calcitriol (1,25-D), is dangerously high due to the immune system response to intracellular bacteria. Testing only the precursor and assuming that a low level indicates a Vitamin D deficiency may result in a misdiagnosis. In this case, supplementing with Vitamin D will provide more 'fuel' for the production of excess 1,25-D by the inflamed tissues. This will allow the bacteria to freely multiply with a resulting worsening of Th1 inflammation.
For information on the effects of elevated 1,25-D, see:
A Review - Vitamin D and Calcium in Sarcoidosis
Hormonal Diagram
Hypervitaminosis-D Symptoms
For those who are interested in the intricacies of Vitamin D metabolism, below is a link to a paper which is an excellent in-depth overview of how the hydroxylase enzymes of the Vitamin D pathway function in both illness and health.
http://www.jbc.org/cgi/content/abstract/280/21/20604
See also The Truth About Vitamin D: Fourteen Reasons Why Misunderstanding Endures
Vitamin D: Production, Metabolism and Mechanisms of Action (This article from an endocrinology textbook is included for background purposes for those interested. Some of it may be superceded by Dr. Marshall's work and other new research.)
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Posted: Tue Oct 11th, 2005 21:51 |
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Vitamin D metabolism and Th1 inflammation
1,25-D is manufactured in the cytoplasm of Th1 activated macrophages by enzymatic conversion of 25-D to 1,25-D. The P450 enzyme involved is CYP-27B1, and the conversion occurs in the mitochondria of the activated macrophages.
This conversion is catalysed 30-fold by the presence of Interferon-gamma, the cytokine characteristic of a Th1 immune reaction.
The mitochondria do not have significant quantities of the enzyme CYP-27A1, which is necessary for 1,25-D to be produced directly from 7-dehydro-cholesterol, which is most probably the pathway that the body preferentially uses when one is isolated by geography or season from ingesting food with Vitamin-D in it. The Vitamin D ingested is converted to 25-D, and it then directly fuels the out-of-control production of 1,25-D in the mitochondria of the Th1 activated macrophages.
Production of 25-D when exposed to sunlight
The keratinocytes of the skin can, by comparison, make 1,25-D directly from 7-dehydro-cholesterol, and they do this when exposed to sunlight. Because the final stage of this reaction is also catalyzed by any Interferon-gamma from any inflammation paracrine to the keratinocytes, any and all 25-D which is made from sunlight is energetically converted to 1,25-D (OK, well, NEARLY all  ). Thus sunlight is not usually a significant contributor to the 25-D levels of Th1 patients.
It is ingested Vitamin D which primarily fuels the over-production of 1,25-D in activated macrophages, and which exerts the immunosuppressive action upon the host.
Ipso facto, when 1,25-D is elevated because a Th1 patient is ingesting Vitamin D, the immune system cannot kill the intraphagocytic bacteria, there is less cytokine release, and the patient feels better and may even become less symptomatic - in the short term. Of course, as far as we know, the bacteria are now (slowly, chronically) multiplying, unhindered, in the cytoplasm of the phagocytes.
Dr. Trevor Marshall, PhD
Macrophages also produce Vit. D in response to UV light (not just keratinocytes) 4/9/2007
UVB-induced 1,25(OH)2D3 production and vitamin D activity in intestinal CaCo-2 cells and in THP-1 macrophages pretreated with a sterol Delta7-reductase inhibitor.
"In conclusion, preconfluent CaCo-2 cells and THP-1 macrophages are able to induce vitamin D activity upon UVB irradiation and hence combine all parts of the vitamin D photoendocrine system, a characteristic which is therefore not keratinocyte specific."
Fish make Vitamin D in the absence of UV light
See for example "Cloning of a functional vitamin D receptor from the lamprey (Petromyzon marinus), an ancient vertebrate lacking a calcified skeleton and teeth"
http://endo.endojournals.org/cgi/content/full/144/6/2704
I personally believe that UV light is not necessary for for Homo sapiens either. Mankind has been hung up on the "sunshine" concept, and has not gone looking for the enzyme which allows the electrocylic cleavage of the sterol ring. So they haven't found it
Standard human logic has failed to understand the steroidal nature of Vitamin D. Biologists are now publishing an average of one paper a day describing the steroidal actions of Vitamin D. But nobody in clinical medicine seems to notice
http://tinyurl.com/2xf2rq
..Trevor..
Bioavailability of D metabolites
D-Binding Protein is the major transporter of vitamin D metabolites in the circulation. Whether 1,25-D is lipid soluble, or exactly what the mechanisms of storage and release by lipids might be, are not yet confirmed. 25-D may be fat soluble, but its bioavailability is primarily regulated by 1,25-D via the DBP.
Fish have a very active D metabolism. The Zebra fish even has two slightly different VDR, each transcribing genes. It is almost certain they would contain a regulation mechanism similar to man. Crush their livers up and you would have a large amount of a mixture of bioactive enzymes,proteins, and sterols (including cholesterol and Vitamin D).
As the 1,25-D levels drop the DBP releases bound 25-D. That is the control mechanism in the bloodstream, and it should work the same way in-vitro as well, since it is effected at the level of a single, or just a handful, of molecules.
..Trevor..
Gene transcription in human cells
Transcription of hundreds of genes by the vitamin D nuclear receptor (VDR) only occurs if the VDR is in homeostasis with the agonist 1,25-D. That means the 1,25-D docks into the VDR as a ligand.
The following is a quote from the text book: Recombinant DNA and Biotechnology by Kreuzer and Massey, page 88.
An example of gene regulation through enhancers is the response of genes to steroid hormones such as estrogen. Estrogen and other steroid hormones pass through the cell membrane and bind to specific receptor proteins inside the cell. When the hormone binds, the receptor changes shape in a way that allows it to move to the nucleus, where the receptor-hormone complex acts as a transcriptional activator by binding specific enhancers. Thus, specific genes are turned on in response to the presence of the hormone.
The problem with 25-vitamin D is that it can also physically bind to the VDR and when that happens the process stops. It is called an antagonist because it cannot activate the VDR like the agonist 1,25-D, so none of the hundreds of genes get transcribed into mRNA. High concentrations of 25-D from supplementing can displace 1,25-D stopping the process.
"The way the bacteria stop the VDR from transcription is to produce ever-increasing concentrations of an antagonist, such as Capnine, which ultimately stop 1,25-D from activating the VDR. In this way the bacteria stop the VDR from tanscribing most of the antimicrobial peptides."
..Trevor..
A Brief Overview of Innate and Adaptive Immunity in Relation to the Marshall Protocol
Last edited on Mon Mar 3rd, 2008 09:32 by Foundation Staff
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Posted: Sat Oct 15th, 2005 05:23 |
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Vitamin D studies in Th1 inflammation
Most older women deficient in vitamin D
Vitamin D levels in women with systemic lupus erythematosus and fibromyalgia.
Huisman AM, White KP, Algra A, Harth M, Vieth R, Jacobs JW, Bijlsma JW, Bell DA.
Department of Medicine, University of Western Ontario, London, Canada. Margriet.Huisman@planet.nl
Vitamin D is a seroid hormone precursor. It is not a vitamin. I have seen no studies which definitively demonstrate that it is necessary for human survival.
..Trevor..
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Posted: Sat Oct 15th, 2005 05:29 |
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1,25-D is at the top of the hormone cascade
See http://autoimmunityresearch.org/hormones.pdf
In general, any intervention on a hormone with as widespread effects as 1,25-D is very dangerous indeed. You can see this with the TNF-alpha blockers which, although they do reduce pain and inflammation, have a high rate of lymphoma (cancer) generation and also make the patient extremely susceptible to infection, even to Tuberculosis.
Consequently my approach is always to remove the cause of the problem and let the body rebalance itself. I would doubt that any selective antagonist to 1,25-D could have any effects other than catastrophic failure of body systems. 1.25-D is necessary for proper functioning of nearly every body system. Here is an old drawing from Dr Tony Norman (University of California Riverside), the man who discovered 1,25-D. It is not complete, but will give you some idea of the complexities involved with 1,25-D intervention..
http://vitamind.ucr.edu/Images/metab.gif
Dr. Trevor Marshall, PhD
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Posted: Tue Nov 29th, 2005 00:43 |
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Articles on vitamin D for skeptics
These articles show how D dysregulation can be hard to detect but still can be important (they demonstrate local 1,25 D levels may be elevated to harmful levels, despite average 1,25D levels in blood)
Mawer, EB; Hayes, ME; Still, PE; Davies, M; Lumb, GA; Palit, J; Holt, PJ. Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis. J Bone Miner Res. 1991 6(7), 733-9. This study found that despite low levels of 25D and normal levels of 1,25D in a British population with rheumatoid arthritis (RA), that if given 25D, there was production of 1,25D in the joints of the RA patients by the macrophages just as in sarcoidosis. If the patient was given a large dose of vitamin D, their serum levels went up much more than the controls. On the MP, there is a rheumatoid arthritis patient who was on vitamin D before the MP and got worse on it. She is now considerably better after a year on the MP and with avoidance of D.
Inaba, M; Yukioka, K; Furumitsu, Y; Murano, M; Goto, H; Nishizawa, Y; Morii, H. Positive correlation between levels of IL-1 or IL-2 and 1,25(OH)2D/25-OH-D-ratio in synovial fluid of patients with rheumatoid arthritis. Life Sci 1997 61(10), 977-85. This paper shows that inflammatory chemicals associated with increased disease activity and bone loss were higher when the levels of 1,25D in the joint were higher.
Sambrook, PN; Shawe, D; Hesp, R; Zanelli, JM; Mitchell, R; Katz, D; Gumpel, JM; Ansell, BM; Reeve, J. Rapid periarticular bone loss in rheumatoid arthritis: Possible promotion by normal circulating concentrations of parathyroid hormone or calcitriol (1,25-dihydroxyvitamin D3). Arthritis Rheum. 1990 33(5), 615-22. This study followed RA patients and the majority lost bone near their wrist joint over 2 years. The 3 patients who lost almost no bone were the ones with very low 1,25D.>>
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Posted: Tue Dec 6th, 2005 04:25 |
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1,25 D does not control intracellular calcium concentration
1,25-D does not control intracellular calcium. Here's a summary on this topic from Dr. MM Kahn and Dr. Joan P Desborough:
Intracellular calcium is involved in many intracellular responses to chemical and electrical stimuli and required by many enzymes for full activity. It is controlled by calcium binding proteins; the two best known are troponin and calmodulin. Troponin is involved in muscle contraction, and calmodulin causes configurational changes to proteins and enzyme activation.
Intracellular calcium levels are much lower than outside cells. Calcium entry via specific channels leads to direct effects, e.g. neurotransmitter release in neurones, or further calcium release from intracellular organelles, for example in cardiac and skeletal muscle.
Belinda Fenter
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Posted: Mon Dec 19th, 2005 22:15 |
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Nutritional sources of vitamin D may not be necessary
It used to be accepted that vitamin D was synthesized via the skin, and then metabolized via the liver and kidneys to produce the active hormone D.
Now we know that human skin can completely synthesize the active hormone D, 1,25-dihydroxycholecalciferol, independent of other organs. http://tinyurl.com/65nrc While there is substantial evidence for other extra-renal sources of hormone 1,25-D, it has been known for decades that activated macrophages produce 1,25-D in diseases such as sarcoidosis.
The vitamin D used by the body (1,25-D) comes mostly (90 to 100%) from exposure to sunlight. http://tinyurl.com/4z25e Ten to fifteen minutes of sun exposure two times per week to the face, arms, hands, or back is enough exposure to provide an adequate amount. People can get that in only a fraction of the amount of time they spend driving each week.
We know now that hormone D (1,25-D) activates the immune system. However, the increased use of nutritional vitamin D (25-D)is suppressing the immune systems of people with immune disease who can be made ill by additional vitamin D.
Until we standardize the clinical evaluation of vitamin D metabolites, both 1,25-dihydroxycholecalciferol D and the inactive precursor, 25-dihydroxyvitamin D, we have no idea who actually needs supplemental vitamin D and who has dysregulated vitamin D metabolism, resulting in their suffering excess production of the biologically active metabolite and all the impact of this hormone, which includes activation of the immune macrophage system. http://tinyurl.com/6gbgq
Regarding nutritional sources of vitamin D:
- There is no Recommended Daily Allowance (RDA) for vitamin D, because it is endogenously produced by humans in the presence of a few minutes of sunlight.
- The alternative Recommended Dietary Intake (RDI) of nutritional vitamin D is based on the (assumption of) absence of adequate sunlight. http://www.iom.edu/Object.File/Master/7/296/0.pdf
- When studies of dietary needs for vitamin D are conducted, people with diseases that result in dysregulated vitamin D metabolism (such as sarcoidosis) may be excluded. One example is the Food Standards Agency's Expert Group on Vitamin and Minerals: Safe Upper Levels for Vitamins and Minerals May 2003
http://www.food.gov.uk/multimedia/pdfs/vitmin2003.pdf
Studies have shown that nutritional vitamin D can be toxic to vascular tissues. http://tinyurl.com/45he3 and http://tinyurl.com/44kb4 Vitamin D has been used to induce an animal model of arthrosclerosis in research: http://tinyurl.com/664sv
Too much vitamin D can result in illness ranging from dental changes http://tinyurl.com/66e98,
to bone loss http://tinyurl.com/4m9au or even death. http://tinyurl.com/4cfsg
The standard practice, in assessing vitamin D status, has been to evaluate only serum 25-D, which is the inactive metabolite. The best way to know whether sunlight and vitamin D would be dangerous is to test the two major vitamin D metabolites (25-D and hormone 1,25-D) to detect any evidence of dysregulated vitamin D metabolism.
Belinda Fenter
Vitamin D is an insidious substance. Your body becomes tolerant of it, at the same time it is stopping the immune system from attacking the intraphagocytic pathogens. IMO, If you don't keep your Vit D ingestion near-zero you will not fully recover, although you will be less photosensitive, and you will have herx-like transient symptoms that probably don't contribute to your ultimate recovery.
In many ways, exogenous Vitamin D acts on our body just as exogenous corticosteroids do. It is, after all, a steroid, and it has a ! wide range of effects in the body, acting on many of the same body systems as a corticosteroid.
Unfortunately there are many folks who don't understand the detailed biochemistry needed to appreciate the harm that exogenous Vitamin D does to a Th1 patient. Some listen to the moderators, and some don't. In five years time we will be able to sit down and compare notes, and so better evaluate the relative progress of the two groups. Nevertheless, as far as I can tell right now, the only folks who seem near full-recovery are those who have meticulously followed our suggestion to stay away from Vitamin D and sunlight.
..Trevor..
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Posted: Tue Feb 28th, 2006 06:29 |
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Difficulties inherent in publishing new information about vitamin D metabolism
In the new textbook:
Vitamin D: new research, Veronica D. Stoltz (ed.) New York, Nova Science Publishers. 2006. Please note the following chapter:
"Vitamin D Metabolism in Chronic Disease."Waterhouse JC, Marshall TG, Fenter B, Mangin M, Blaney G
There are a dearth of papers published which describe the immunosuppressive effects of Vitamin D. The people who really know, like Prof Tony Norman, for example, have gotten so much hostility from the clinical medicine folks that they tend to focus on esoteric Biochemistry topics, and avoid clashes with the Vitamin D zealots.
I myself received a threat immediately I started talking about high doses of Vitamin D being harmful. A high-powered, Vitamin-D-advocating University Professor said that he and his colleagues would write to the Editors of any journals which dared to publish any of my research and tell them what a jerk I was. So publishing in this topic is no game, it is big-league. There are a lot of reputations, and money, which will sink when the true behaviour of Vitamin-D supplementation becomes understood.
Joyce Waterhouse, together with several of us, has written a chapter for a new textbook called "Vitamin D: New Research." It won't be printed for another several months, unfortunately, as this would give your physician much of the data on Vitamin D's actions which he/she seeks. The full citation is:
Waterhouse JC, Marshall TG, Fenter B, Mangin M, Blaney G: High levels of active 1,25-dihydroxyvitamin D despite low levels of the 25-hydroxyvitamin D precursor - Implications of dysregulated vitamin D for disgnosis and treatment of Chronic Disease. In Vitamin D: New Research. Volume 1. Edited by: Stoltz VD. New York: Nova Science Publishers; 2006. ISBN: 1-60021-000-7 (click here for publisher's website)
Dr Greg Blaney (one of the authors) is located in BC,CA, and I am sure he would be happy to talk with your Doc about the clinical issues.
I have also studied the actions of Vitamin D at the molecular level, and our recent paper provided a clear reminder of the importance of the VDR in the immune system. There are several citations listed in that paper which might be helpful.
The very best exposition of the complexity (and, at the same time, sheer elegance) of the Vitamin D metabolism is
Bikle DD: Vitamin D: Production, Metabolism, and Mechanisms of Action. In "Diseases of Bone and Calcium metabolism" (Editor: Arnold A) Endotext.org
See our chapter in "Vitamin D: New Research," and Dr Marshall's most recent writings on VDR and innate immunity, which is at this URL
http://www.marshallprotocol.com/forum39/5940.html
Our new book chapter is on the Internet
A copy of the chapter can be found at this Internet address:
http://winmlm.neostrada.pl/vitamindbook/vitamindnewresearch.pdf
Dr. Trevor Marshall, PhD
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Posted: Tue Mar 7th, 2006 01:58 |
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Activation of the VDR is necessary for calcium to be absorbed from the gut
There have been some papers recently which showed that, in murine models, the VDR was necessary for calcium to be absorbed from the gut. The VDR is solely activated (we currently think) by 1,25-D; and de-activated by Vit-D; 25-D; 24,25-D; 25,26-D; and the corticosteroids.
"New insights into mineral and skeletal regulation by active forms of vitamin D"
http://tinyurl.com/9j5rr
"Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats."
http://tinyurl.com/bdbpr
Indications that the VDR is also the driving factor for the calcium metabolism in man has also been popping up, for example:
"Vitamin D receptor Fok1 polymorphisms affect calcium absorption, kinetics, and bone mineralization rates during puberty"
http://tinyurl.com/bsd8r
The future is not looking good for those experts who still maintain that Vitamin D has a "Genomic" mechanism and a "non-Genomic" mechanism of action in the body. This distinction was originally introduced so that the 'genomic' actions of the VDR on the immune system could be compartmentalized from the classical theory of vitamin-D's action on calcium. But the ice under this theory is getting thinner every day... It sure looks like our bodies are driven by 'the Genome,' these days...
..Trevor..
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Posted: Tue Mar 7th, 2006 02:45 |
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Epidemiological study finds a strong association between high 1,25 D levels and osteoporosis.
The Danish epidemiologist Brot studied 500 healthy women ( that is they were not drawn from a population with particular health issues) aged 42 to 58 and concluded that in this group bone density was strongly inversely proportional to 1,25 D levels ( that is low bone density was strongly associated with high 1,25 D levels) and only rather weakly directly proportional to 25 D levels. The sample was chosen randomly - and was not done to test the impact of any particular treatment programme.
Relationships between bone mineral density, serum vitamin D metabolites and calcium:phosphorus intake in healthy perimenopausal women.
Brot C, Jorgensen N, Madsen OR, Jensen LB, Sorensen OH.
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Posted: Tue Mar 21st, 2006 03:32 |
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All D-metabolites are seco-steroids
I am comparing Vitamin-D3 to Prednisolone. The metabolism goes thus:-
7-dehydrocholesterol >> Vitamin-D3 >> 25hydroxyvitamin-D >> 1,25dihydroxyvitamin-D
At each 'hydroxy' stage an oxygen (and hydrogen) are added. You need the hydroxy at the 1-alpha position (designated as O1 in Figure 5 of our recent paper) in order to activate the VDR. Only 1,25-D has that. You also need the hydroxy group at the C25 position (in Figure 5 you can see that hydrogen-bonding to HIS305 and HIS397).
All the metabolites are seco-steroids, as I demonstrate on the video.
..Trevor..
A 'RealVideo 9' version of the DVD of Dr.Marshall's FDA CDER presentation is available online at url
http://autoimmunityresearch.org/fda-visiting-professor-7mar06.ram
The original DVD of the presentation can be requested from
http://autoimmunityresearch.org/fdacder.htm
"Marshall TG: Molecular genomics offers new insight into the exact mechanism of action of common drugs - ARBs, Statins, and Corticosteroids. FDA CDER Visiting Professor presentation, FDA Biosciences Library, Accession QH447.M27 2006"
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Posted: Mon Apr 10th, 2006 15:05 |
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(filelink)
VDR Nuclear Receptor Competence is the Key to Recovery from Chronic Inflammatory and Autoimmune Disease
Dr. Marshall:
I recently wrote a brief abstract collecting my current thoughts on the MP, which I submitted to an upcoming conference on Chronic Disease. I wanted to let you know my latest thinking about Th1 disease (and give you all an opportunity to 'peer-review' it).
You will note that the intense research I did prior to my FDA presentation helped me see both the Vitamin D deprivation and the Benicar blockade as being one-and-the-same in their effect, as they both enable the VDR nuclear receptor to do its job as the primary activator of innate immunity (remember that "innate immunity" is the 'last line' of defence, while "acquired immunity" is the first line, driven by the generation and recognition of antibodies, etc - it is innate immunity alone that can protect against intraphagocytic pathogens).
Here it is...
VDR Nuclear Receptor Competence is the Key to Recovery from Chronic Inflammatory and Autoimmune Disease
The VDR Nuclear Receptor is at the heart of human innate immunity, responsible for TLR2, TLR4, CAMP, TACO and IL2 expression[1]. During Th1 immune challenge, the VDR is activated by the endogenous secosteroid 1,25dihydroxyvitamin-D. We have previously described how intra-phagocytic bacterial pathogens are responsible for much chronic inflammatory disease[2,3], and our phase 2 study results have confirmed this pathogenesis. In order to induce recovery from chronic inflammatory disease, it is necessary to restore VDR functionality by removing all exogenous sources of the secosteroid we call ‘Vitamin-D’, and dampen down over-exuberant VDR activity, for example with the ARB Olmesartan[1]. This enables the immune system to recognize the pathogens. To date we have demonstrated recovery from Hashimoto’s Thyroiditis, Rheumatoid Arthritis, Sarcoidosis, and an assortment of chronic inflammatory diagnoses. This breakthrough is the result of a collaboration between molecular scientists and a disparate group of innovative physicians, facilitated by the Internet. However, the widespread application of this pathogenic understanding will require meticulous translation of the molecular science into conventional clinical precepts.
1. Marshall TG: Molecular genomics offers new insight into the exact mechanism of action of common drugs-ARBs, Statins, and Corticosteroids. FDA CDER Visiting Professor presentation, FDA Biosciences Library Accession QH447.M27 2006.
(Video DVD transcript can be ordered, and a low-resolution version is online at
http://AutoimmunityResearch.org/fda-visiting-professor-7mar06.ram)
2. Marshall TG,Marshall FE: Sarcoidosis succumbs to antibiotics-implications for autoimmune disease. Autoimmunity Reviews,2004;3(4):295-3001.
(Fulltext at http://yarcrip.com/sarcoidosissuccumbs-preprint.htm )
3. Marshall TG,Fenter B,Marshall FE: Antibacterial Therapy Induces Remission in Sarcoidosis. Herald MKDTS 2004g;Volume.III:Release.1(The Journal of the Interregional Clinical-Diagnostic Center, Kazan, in Russian translation).ISSN:1726-6149.
(English version at http://www.joimr.org/phorum/read.php?f=2&i=107&t=107 )
===========================================
A simple clarification of the above abstract:
1,25-D is the only metabolite that turns the VDR on.
Everything else turns it off, or at least modifies its capabilities. So exogenous Vitamin D and 25-D both bind into the VDR and block it from working properly. They will displace any 1,25-D from the receptor in a dose-dependent manner. The higher the concentration of Vitamin-D or 25-D competing with the endogenous 1,25-D the more of that 1,25-D will be displaced from the VDR. That occurs in a manner represented by the displacement graphs in the FDA presentation.
Benicar also stops the over-excitation of the VDR by inactivating it, but it does so in a dose-dependent and controllable manner. We control Benicar's activity against the VDR by varying the Benicar dose. But Benicar also has profound actions elsewhere in the immune system. Some I am already aware of, some I am not.
..Trevor..
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The Abstract has been accepted for poster presentation at the 2006 "Days of Molecular Medicine" conference in May, at Karolinska Institut in Stockholm.
http://www.nature.com/nm/meetings/dmm/index.html
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Posted: Mon Apr 17th, 2006 20:55 |
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| You do not need to ingest Vitamin D to be healthy (click here)
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Posted: Thu Aug 24th, 2006 05:30 |
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The effect of 25-D on the vitamin D Receptor
(filelink)
The displacement of a ligand from a receptor is reversible. If the concentration is high enough, 25-D will displace either 1,25-D or Benicar from the VDR LBP, and the reverse is also true, Benicar will displace 1,25-D and 25-D from the LBP, based on relative concentrations.
It is certain that the layout of the Olmesartan oxygen atoms in the vicinity of the key SER278 / TYR143 / ARG274 / SER237 VDR residues is that of an agonist. That is, when Benicar docks into the VDR displacing 25-D and 1,25-D it at least partially activates the VDR. The higher the Benicar dose the greater percentage of the Ds will be displaced, according to the standard displacement curve in my FDA presentation slides.
25-D displaces 1,25-D from the Vitamin D Receptor. Too much 25-D is able to turn off the immune system response which is necessary to prevent chronic inflammatory disease.
..Trevor..
The level of 25-D2 and 25-D3 that the body creates from ergosterol and 7-dehydrocholesterol is regulated by a complex control system, outlined in Figure 1 of my "Vitamin D Discovery.." paper. If the person was severely ill then the body would be fighting hard to prevent conversion, and would down regulate the amount of 25-D produced. If the person was healthy, a reasonable proportion would be converted, enough to make sure the VDR is fed with the appropriate amount of 1,25-D to enable gene transcription.
Ergosterol, 7-dehydrocholesterol and 25-D all are equally immunosuppressive when they enter the cytoplasm. Indeed, since the concentration of 25-D is regulated by the D-Binding Protein, the presence of the precursor ergosterol may be even more immunosuppressive than 25-D, depending on DBP, and a number of factors yet to be more fully understood.
..Trevor..
See also:
The Need for a Benicar Blockade
Last edited on Sun Jul 27th, 2008 09:07 by Foundation Staff
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Aussie Barb
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Posted: Mon Aug 28th, 2006 22:51 |
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(ricketsfilelink)
Rickets (Osteomalacia)
Vitamin D does not cause or cure rickets. The USDA says: "It is not due to vitamin D deficiency but is caused by not having enough calcium in the diet"
http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=169216
There are studies implicating hypophosphatemia as well, but not Vitamin D. See also Vitamin D Doesn't Cause or Cure Rickets (Hypophosphaemia Causes Rickets). And Rickets is not cured by vitamin D (click here for Dr. Marshall's perspective)
We have been looking into the new discoveries about rickets. It is now certain that rickets is not caused by a lack of Vitamin D, but by a lack of dietary calcium and phosphorus.
Just this morning I found this study on mice
http://tinyurl.com/z7k2s
which confirmed this big government study
http://tinyurl.com/l63hk
which concluded: rickets "is not due to vitamin D deficiency but is caused by not having enough calcium in the diet"
Not only is rickets is not caused by a lack of Vitamin D, but you don't need to supplement Vitamin D in order to cure it.
I would rate that as the second biggest mistake in medical history - the first was calling 'vitamin D' a 'vitamin'
You might also be interested in looking over a paper from 1857, a paper which pointed away from Vitamin D as the cause of rickets.
http://ije.oxfordjournals.org/cgi/content/full/32/3/336
VITAMIN D SCHEMATIC
http://chorus.rad.mcw.edu/doc/00659.html
7-DHC -----> D3 -----> 25-OH vit D3
-----> 1,25-OH vit D3
(1) skin.....sunlight converts 7-dehydrocholesterol to vit D3 (cholecalciferol)
(2) liver.....25-hydroxylation
(3) kidneys.........1-hydroxylation to active form
requires parathyroid hormone (PTH)
- vit D promotes calcium absorption from bowel
- deficiency ==> rickets
http://www.biochemj.org/bj/034/0538/0340538.pdf
"It is now a matter of common knowledge that the rickets so produced can be largely, if not completely, healed by the addition of phosphates to bring the Ca ratio more nearly equal to 1."
Calcium and Vitamin D: what is known about the effects on growing bone.
Demay MB, Sabbagh Y, Carpenter TO. Pediatrics. 2007 Mar;119 Suppl 2:S141-4. 50 Blossom St, Thier 11, Boston, MA 02114.
The objective of these investigations was to determine if the receptor-dependent effects of 1,25-dihydroxyvitamin D were essential for normal skeletal growth. Mice with targeted ablation of the vitamin D receptor were engineered, and the skeletal consequences of vitamin D receptor ablation were studied in the presence of normal and abnormal mineral ion homeostasis. Prevention of abnormal mineral ion homeostasis resulted in the development of a normal skeleton in the absence of a functional vitamin D receptor. The metabolic cause of rickets was found to be hypophosphatemia. The major receptor-dependent actions of
1,25-dihydroxyvitamin D on skeletal development are indirect and are a reflection of the role of this hormone on intestinal calcium absorption.
..Trevor..
See also:
Don't I need to take a calcium supplement?
Vitamin D deficiency does not cause rickets.
Last edited on Sun Oct 19th, 2008 05:42 by
____________________
Barb: Dx Inflammatory Disease Endocrine Imbalance 2003| Depression| 24+ years not Dx| MP Aug04| ABC of MP| MP Search|
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Posted: Thu Oct 19th, 2006 03:20 |
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Stores of vitamin D gradually drop
(filelink)
Both 25-D2 and 25-D3 occur naturally in certain foods. 25-D3 (cholecalciferol) is chemically synthesized and added to food as a vitamin D supplement. 25-D2 (ergocalciferol) isn't usually added to dietary sources.
The body makes 25-D3 from 7-dehydrocholesterol. Production of 25-D3 from 7-dehydrocholesterol is regulated by the immune system. So the Vitamin D Receptor(VDR) tries to down-regulate the amount of 25-D being made available whenever the 1,25-D gets too high.
If you look at this paper
http://www.annals.org/cgi/content/full/127/3/203
you will find a graph Fig 1
http://www.annals.org/cgi/content/full/127/3/203/F1
with a graph of 25-D vs time for 4 patients recovering from Vit D 'poisoning.' Note that the time axis is in years.
..Trevor..
Bioavailability of D metabolites
D-Binding Protein is the major transporter of vitamin D metabolites in the circulation. Whether 1,25-D is lipid soluble, or exactly what the mechanisms of storage and release by lipids might be, are not yet confirmed. 25-D may be fat soluble, but its bioavailability is primarily regulated by 1,25-D via the DBP.
Fish have a very active D metabolism. The Zebra fish even has two slightly different VDR, each transcribing genes. It is almost certain they would contain a regulation mechanism similar to man. Crush their livers up and you would have a large amount of a mixture of bioactive enzymes,proteins, and sterols (including cholesterol and Vitamin D).
As the 1,25-D levels drop, the DBP releases bound 25-D. That is the control mechanism in the bloodstream, and it should work the same way in-vitro as well, since it is effected at the level of a single, or just a handful, of molecules.
This means that for some folks, it takes a long time to reduce levels of 25-D even with strict dietary compliance.
The stores of D gradually drop, it just takes time. Meanwhile, if your immune system is reacting then you will be progressing fine. Just be aware that one day the 25-D will drop, and as it drops your immunopathology will increase, and may need to reduce the abx dose. So it is best to have the D measured every 2-3 months.
..Trevor..
As Dr. Marshall discusses in his BioEssay, one of the things that determines the level of 25-D measured, is the amount of vitamin D that is converted to 25-D. That conversion is affected by many factors including the level of 1,25D. Higher 1,25D reduces conversion of vitamin D to 25-D (so lower 1,25D would result in greater conversion to 25-D). So, that could be playing a role -- and there are many complex inter relating factors, as you can see in the Figure 1 with the arrows in the article:
http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf
Members' experiences
-I have been on the MP for a year now and, FINALLY, my 25-D is coming down. My pre-MP numbers (July ’04) were: 32 for 25-D and 65 for 1,25-D. In the two years prior to the MP, at the direction of my doctor, I took massive doses of vitamin D -- as much as 2400IU per day. That’s the amount of D in 5 dozen eggs! Even though I stopped the supplementation in July ’04 and began closely watching my diet and diligently cave dweller in the weeks that followed, that 25-D would not budge! Then, whoosh! A drop into the teens!
July ’04 32
Sept ’04 35
Dec ’04 34
Mar ’05 27
Aug ’05 16
Hang in there friends. My 25-D came down and yours will too. ~Carol
See also Measurement of D2 and D3
Last edited on Sun Feb 3rd, 2008 08:21 by Foundation Staff
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Posted: Sat Dec 23rd, 2006 15:43 |
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Skin color
(filelink)
Your supposition (that dark skin is somewhat protective when it comes to 1,25D levels generated by sunlight) relies on the (widely believed) assertion that 1,25-D can only be made by the body from 7-dehydro-cholesterol under the action of sunlight. That is not correct.
There are hundreds of folks on the MP who have been getting no UVB at all, for a period of years. Yet they are manufacturing more than enough 1,25-D to keep their innate immune systems ticking.
The concept that humans need sunlight falling on skin to produce 1,25-D, even though many nocturnal mammals do not, is, even by itself, ludicrous. Now that we understand the molecular genomics of the biochemical reactions it just makes the concept even more ludicrous.
There are social and societal differences between communities which do play into the pathogenesis of these Th1 diseases. Those are what need to be studied, not the color of the skin
..Trevor..
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Posted: Sun Jan 14th, 2007 17:18 |
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(filelink)
Political climate affects the way vitamin D is studied and perceived
The key thing to remember about vitamin D is the political climate which surrounded the discovery of 1,25-dihydroxyvitamin-D by Tony Norman
http://biochemistry.ucr.edu/faculty/norman.html
There was extremely aggressive patent litigation, with the result that Tony lost the 'invention right' to DeLuca. As a result you ended up with two camps. The clinical arm, represented by the work of DeLuca and Holick, whose research was generally funded by the manufacturers of vitamin D, and the theoretical molecular chemists, like Tony Norman, who continued to dig down deep into exactly what this secosteroid hormone does in the human body.
..Trevor..
The researchers whom we have entrusted as 'experts' in Vitamin D, Rickets, and Osteoporosis have all done a terrible, terrible job.
Rickets is not caused by lack of Vitamin D. It is caused by hypophosphatemia. Osteoporosis is not caused by low Vitamin D, it is caused by a weakness in the bone matrix due to a number of factors, Estrogen being high in importance.
The mistaken notion that this secosteroid is a vitamin has endured for generation after generation because of poor science, money for grants provided by the manufacturers, and just plain bloody-mindedness that this substance somehow had to be good, because it had been called a vitamin.
This has blinded clinical medicine to the true role of the substance, as a transcriptional activator which helps turn DNA into protein. It is at the very heart of the human innate immune system (but not of mice), responsible for the transcription of the majority of antimicrobial peptides, the body's defense against pathogens. It transcribes genes ranging from Down Syndrome to Cancers. It is responsible for DNA transcription of at least 1000 genes, and as many as 27,000 genes.
IMO The last 100 years will be regarded by history as the darkest period in the history of medical science, primarily because of medicine's terrible mistake in failing to recognize this substance as a steroid transcriptional activator, and not a vitamin, and the subsequent spread of obesity, cardiovascular disease, diabetes, infectious and 'autoimmune' diseases which have been caused by its precipitate administration in staple foods of the population.
Look at all these papers being written about the way that Vitamin D really works
http://tinyurl.com/2cbzha
- an average one paper a day is coming out of molecular biology about the role of the Vitamin D receptor. Yet clinical medicine is so wedded to the misguided notions of the past that it has shut itself off from trying to understand the truth.
Sigh...
..Trevor.. (Aug 07)
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Posted: Fri Jan 19th, 2007 06:14 |
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(filelink)
1,25-D is immunosuppressive
http://www.nature.com/ki/journal/v61/n1/full/4492730a.html
Kidney International (2002) 61, 288–296; doi:10.1046/j.1523-1755.2002.00101.x
1,25-Dihydroxyvitamin D3 shows strong and additive immunomodulatory effects with cyclosporine A in rat renal allotransplants
Claudio A Redaelli, Markus Wagner, Daniela Günter-Duwe, Ying-Hua Tian, Philip F Stahel, Luca Mazzucchelli, Ralph A Schmid and Martin K Schilling
"Vitamin D3 and its metabolites have long been found to exert immunosuppressive effects both in vivo and in vitro."
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Posted: Thu Feb 8th, 2007 07:06 |
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(filelink)
Study shows Vit D upregulates cathlecidin
It (study by Liu) suggests that for a general population of patients (presumably only reflecting the 3 percent that suffer from th1 disorders) Vit D upregulates cathlecidin which is antimicrobial, specifically with regard to TB mycobacteria.
It now seems that an increasing number of doctors think this means that injectible Vit D should be used for both prevention of bacterial infection and treatment for those who are infected. Based on the study, at least one rheumatologist is now administering megadoses of Vitamin D to a Lyme-RA patient. ~jdc
Dr. Marshall replies:
In May 2006 I gave a presentation to members of Team Nobel at Karolinska Institute during DMM2006. It succinctly defines each one of the issues you are asking about. Take another look at
http://autoimmunityresearch.org/karolinska-handout.pdf
Late last year I also covered this topic in detail during my presentations to the physicians of the American Academy of Environmental Medicine and the biochemists at Melbourne University, presentations which can be found on the "Science" DVD from the Foundation, and which you can also find in my "perspectives" section of this study site. Please take a good look at the overview there.
You can also find written transcripts at URLs
http://autoimmunityresearch.org/transcripts/marshall_aaem_2006.pdf
http://autoimmunityresearch.org/transcripts/marshall_bio21_2006.pdf
The VDR is responsible for expressing, or repressing, about 913 genes, and Cathelicidin is just one of them. Among the others are the beta-Defensin anti-microbial peptides, the Estrogen receptor and the Glucocorticoid receptor. It is laughable to simplify the issues as your physicians seem to have done, by looking only at LL-37.
And thats really all I can say. If folk feel that what I have published is incorrect, then they need to put their thoughts into a format which other scientists can understand. Third party transmissal, via somebody like yourself, is just not good enough. All they need to do is pick up the phone, and I will be happy to walk them through the issues.
Vitamin D is a steroid. It acts upon the Glucocortioid receptor as a ligand, not just during the receptor's expression. Those are the functions of a steroid, not a vitamin. Ingested (or injected) Vitamin D suppresses the immune system, making people feel better in the short-run. In the long-run their disease progresses more rapidly, exactly as if they had been given Dexamethasone. There is one paper a day being published into PubMed exploring the functions of the Vitamin D Receptor, the VDR. I try to keep up with them all. I would hope that the rheumatologist who is putting his faith in Liu, et al, also works through, and comprehends, each and every one of these studies.
Murine studies of VDR are flawed
July 08 "The science now explains why mice can never emulate Human Chronic disease, including Cancers. There have been no major breathroughs from murine work, and I now know why there will be none.
Reason 1: The Mouse VDR does not transcribe either the Cathelicidin or the beta-Defensin anti-microbials. The human VDR does. When a microbe knocks out the mouse VDR it does not knock out these antimicrobial defenses, as it does in man.
Reason 2: The VDR binding pocket homology between mice/rats and humans is poor. Drugs will act differently in the two VDR."
..Trevor..
Last edited on Thu Jul 17th, 2008 20:47 by Foundation Staff
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