The integration gurus speak only and exclusively of the "problem" VITAMIN D "low", but completely overlook the big picture. Among the many things that they overlook are the hormone receptors (improperly called "VITAMINA") D. The VDRs: VITAMIN D RECEPTORS!

In the image that I randomly downloaded by doing a trivial search on google, you can see just a small part of the CRUCIAL role that the VDRs have in the metabolism of VITAMIN D (especially when the "expert" doctor on VITAMIN D diagnoses you with "shortage").

Today it is becoming increasingly clear that attempting to test for and correct for so-called vitamin D "deficiencies" is far more complicated than simply looking at 25-hydroxyvitamin D (storage vitamin D) levels and then using oral vitamin D3. This approach fails to recognize the fact that many factors mediate how 25-hydroxyvitamin D is converted to the active secosteroid hormone calcitriol (1,25-dihydroxyvitamin D). Furthermore, numerous pathogenic influences will alter the intracellular transport of calcitriol and nuclear binding to the vitamin D receptor (VDR).

Without EVER investigating these influences, doctors overlook the underlying origins of vitamin D's aberrant activities.

The activation of VDR is ESSENTIAL for a correct functioning of the neuro-endocrine-immune system.

Vitamin D in its active form, calcitriol, is of great importance for many physiological functions. These functions are activated when calcitriol binds to the nuclear VDR receptor site.

Activation of the vitamin D receptor (VDR) is essential for example in:

• Modulation of immune T-cell and B-cell behavior – T-cell lymphocytes are a crucial component of the immune system. They can be both pro and anti-inflammatory. Calcitriol (1,25 dihydroxyvitamin D) can reduce the proliferation of pro-inflammatory cytokines (interferon-gamma and IL-17). Calcitriol can activate more of a TH2-type response through IL-4 and IL-10, as well as promote anti-inflammatory regulatory T cells (TREG) (5).
• Mast Cell Inhibitory Effects – Calcitriol has been shown to inhibit mast cell behavior in vitro (6). Mast cells are a type of immune cell in tissues, which among other functions release histamine, an inflammatory molecule. MCAS (Mast Cell Activation Syndrome) involves increased mast cell degranulation and associated symptoms.
• CYP3a4 activation – VDR can activate CYP3a4. CYP3a4 is the most abundant cytochrome P450 enzyme in the liver. About 60% of hydroxylation reactions in the liver involve CYP3a4. Thus CYP3a4 plays a significant role in hepatic metabolism, detoxification reactions and drug metabolism. CYP3a4 also plays an essential role in the formation of the sex hormones estriol (E3) and 16OHE1 and 16OHE2. The VDR has been shown to influence hepatic CYP3a4 activation (8, 10), as well as intestinal CYP3a4 (9).
• Metabolism of calcium and phosphate – Calcitriol interacts with PTH (parathyroid hormone) to absorb calcium from the intestine and reabsorption of calcium in the kidneys, as well as regulate the excretion of inorganic phosphate.
• Formation of bile acid – Lithocholic acid bile acid can activate the vitamin D receptor (VDR) (15). Lithocholic acid is able to inhibit the TH1 branch of the immune system (16).
• Neuronal growth and integrity – NGF (nerve growth factor) is enhanced by activation of the VDR receptor. This is significant because ß-amyloid plaque inhibits VDR (17).
• Activation of the dopamine pathway – Activation of calcitriol and VDR leads to the activation of the dopamine pathway via tyrosine hydroxylase (18).
• Testosterone, sperm count and fertility – VDR activation interacts with sexual reproductive processes, including androgen receptor function, testosterone synthesis, and gonadal sufficiency (19).

The Battle for the Vitamin D Receptor (VDR)

Receptor that “vibrates” to the rhythm of the vibrations of the earth…

Calcitriol (1,25-dihydroxyvitamin D) is the active hormone that binds to the vitamin D receptor (VDR) in the cell nucleus. Once calcitriol binds to the VDR, the vitamin A (retinol) receptor (RXRA and RXRB) is involved in the activation of VDR targets. Thus, vitamin D and vitamin A are truly joined as Siamese brothers. I just remember that preformed VITAMIN A is found ONLY AND EXCLUSIVELY IN ANIMAL FOOD.

The VDR has an important role to play in mitochondrial function and programmed cell death. BCL-2, is a protein involved in the pathways of apoptosis (programmed cell death) and mitochondrial membrane regulation. Up-regulation of BCL-2 is found in cancer, where it prevents cancer cells from undergoing apoptosis. BCL-2 interacts with VDR, leading to its reduced expression (11). The meaning here is that apoptosis is required to inhibit the division and growth of cancer cells. It plays a primary role in gene transcription and proper recirculation of calcium metabolism for bone health and muscle function…and much, much more.

Pathogenic influences are known to negatively affect vitamin D receptor function. This is especially true for:

EBV (so-called and never isolated "virus" of epstein-barr) (1) (still remains an infection)
CMV (so-called "cytomegalovirus") (2) (same speech as above)
Borrelia burgdorferi (Lyme bacteria) (3)

These pathologies have exploded with the explosion of technology:

EPSTEIN-BARR VIRUS IN THE MODERN WORLD.

Wi-Fi radiation (electrosmog) has been shown to negatively affect VDRs (4).

Gliotoxin, the so-called “virulence factor” and mycotoxin of fungi (20). Gliotoxins are produced by many fungi. Although the cited study identified gliotoxin release from Aspergillus fumigatus, it is known that gliotoxins can also be produced by penicillium and trichoderma,

Etc…

Autoimmune thyroid and VDR

In Hashimoto's autoimmune thyroiditis, a common symptom is hair loss. A probable cause for this is inactivation of the vitamin D receptor (VDR). In alopecia (hair loss), very strong associations have been found with VDR inactivation (12). One theory as to why this is happening with Hashimoto's is related to the strong association between Epstein Barr infection (EBV) and autoimmune thyroid disease (13). These infections can cause an inactivation of the VDR (1) and studies have found strong associations between EBV and autoimmune thyroid. Another relationship between Hashimoto's thyroiditis and VDR is through exposure to endotoxins from gram negative bacteria. Endotoxins can induce a cellular danger response (CDR), which causes an upregulation of an enzyme known as 24α-hydroxylase (CYP24a1). Activation of 24α-hydroxylase leads to the formation of an inactive form of calcitriol known as 24,25-dihydroxyvitamin D3 (14).

Hashimoto's hypothyroidism and VDR genetics

A recent study identified the VDR gene as associated with that of Hashimoto's. Carriers of the AA genotype of VDR FOKI had a higher prevalence of Hashimoto's than controls. Interestingly, carriers of the genotype had higher levels of 25-OHD than non-hypothyroid controls.

This again illustrates the futility of 25-OHD level tests (21) (at least by themselves for diagnostic purposes). "Wrong" analysis is almost inevitably followed by a wrong "cure" with potential problems for the patient and iatrogenic error is the third CERTIFIED cause of death in the western world not by chance.

You see how the "experts", instead of practicing tartar ablation, recommend the "VITAMIN D" test without specifying which one, together with a whole other series of very expensive tests. Some of these analyzes seem to have been studied on purpose to then "draw up" a list of supplements to be taken that not even taking out a 30-year mortgage is enough. When the solution always offers it for free, Nature.

Abnormal conversion of calcitriol (1,25 dihydroxyvitamin D)

Immune macrophages in sarcoidosis, a granulomatous disease, have been shown to be involved in the hyperconversion of calcitriol, leading to increases in serum (7). If you have an “overconversion” of 25OH to 1,25OH, you will inevitably be misdiagnosed as having hypovitaminosis D… If you know what I mean.

Indeed, an interesting clinical finding is that among individuals with chronic diseases such as Lyme disease and autoimmune diseases and all inflammatory diseases, both chronic and acute (including COVID), there is a tendency to have significantly elevated calcitriol levels. and “low” 25OH levels.
And this trend is repeated in practically the entire western population who suffer minimally from low-grade inflammation due to chronic exposure to technology and NOTHING exposure to Nature, then also passing from bad food and many other things.

CONCLUDING:

Inactivation of the VDR would theoretically disrupt the intracellular conversion and transport of vitamin D to calcitriol and its subsequent VDR target. After this speech, even a child would understand that taking VITAMIN D, when the problem is its receptor, is the dumbest thing you can do.

If you take 100 people with inflammatory diseases, 99 of them have the active form of VITAMIN D off the charts and the low storage form (which is the only one the "experts" measure). And the only one that also has the low active form? It doesn't have a "vitamin D" problem per se, but a hydroxylation problem to correct. In this case, together with your doctor, you can evaluate therapy with ONLY the active form of VITAMIN D (possibly).

HOW ARE THE VDR REACTIVATED?

In short: if you are fit and healthy you might consider doing preventative cycles with our VDR supplement: the only supplement in the world designed for the metabolism of VITAMIN D but WITHOUT VITAMIN D. In addition, change your lifestyle by getting closer to NATURE, as well as changing your diet (anti-inflammatory) and exploiting biohacking techniques to keep technology in your life under control.

The dumbest solution?

The integration of VITAMIN D3… As increasing ilo 25OHD3 obtains 2 "results":

a- immunosuppressive action, you think you're better but it's just a "honeymoon", the inflammation increases and you don't even notice it.
b- the 25OHD3 is more "similar" than the 1,25OHD3 to the VDRs and further blocks them, preventing them from making even the minimum wage... In short, a dog chasing its tail endlessly!

If you are not healthy and have pathologies such as those described above, you must consult a good doctor who knows these issues, I understand that unfortunately there are very few. I personally don't know any of them. Someone overseas.
For example, I have never heard a doctor ask a patient how he sleeps; how he approaches technology, if he has ever checked the electrosmog in the environment where he lives; I've never heard him prescribe sunbathing all year round, especially without sunglasses and without using absurd (and often toxic) sunscreens.

All of this is, in short, our 360° work of information and scientific dissemination.

VDR

CURCUMIN AND VITAMIN D – IN ONE WORD: VDR!

OUR BOOKS:

VITAMIN D - INSOMNIA. THE EVIL OF THE NEW CENTURY and THE NEW LIVING ACCORDING TO NATURE together !!!!

In the book VITAMIN D, there is obviously a very long discussion on the "VDR" theme for those who wish to deepen it.
I ALSO RECOMMEND IT TO PROFESSIONALS WHO WANT TO GET IN THE GAME WITH HUMBLENESS.

REFERENCES:

1. Yenamandra SP1, Hellman U, Kempkes B, Darekar SD, Petermann S, Sculley T, Klein G, Kashuba E. Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes. Cell Mol Life Sci. 2010 Dec;67(24):4249-56. doi: 10.1007/s00018-010-0441-4. Epub 2010 Jul 1.
2. Rieder FJJ1, Gröschel C2, Kastner MT1, Kosulin K3, Laengle J4, Zadnikar R5, Marculescu R5, Schneider M1, Lion T6, Bergmann M4, Kallay E2, Steininger C7. Human cytomegalovirus infection downregulates vitamin-D receptor in mammalian cells. J Steroid Biochem Mol Biol. 2017 Jan;165(Pt B):356-362. doi: 10.1016/j.jsbmb.2016.08.002. Epub 2016 Aug 9.
3. Salazar JC, Duhnam-Ems S, La Vake C, et al. Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and -independent responses which include induction of IFN-beta. PLoS Pathog. 2009;5:e1000444.
4. Trevor G. Marshallcorresponding author1 and Trudy J. Rumann Heil; Electrosmog & autoimmune disease: Immunol Res. 2017; 65(1): 129–135
5. Margherita T. Cantonna,1,2,* Lindsay Snyder,1 Yang-Ding Lin,1 and Linlin Yang; Vitamin D and 1,25(OH)2D Regulation of T cells; Nutrients. 2015 Apr; 7(4): 3011–3021 .
6. Toyota N1, Sakai H, Takahashi H, Hashimoto Y, Iizuka H. Inhibitory effect of 1 alpha,25-dihydroxyvitamin D3 on mast cell proliferation and A23187-induced histamine release, also accompanied by a decreased c-kit receptor. Arch Dermatol Res. 1996 Oct;288(11):709-15.
7. Barbour GL, Coburn JW, Slatopolsky E, Norman AW, Horst RL. Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N Engl J Med. 1981 Aug 20;305(8):440-3.
8. Lionel Drocourt, Jean-Claude Ourlin, Jean-Marc Pascussi, Patrick Maurel and Marie-José Vilarem; Expression of CYP3A4, CYP2B6, andCYP2C9 Is Regulated by the Vitamin D Receptor Pathway in Primary Human Hepatocytes: Journal of biological chemistry July 12 2002
9. Pavek P1, Pospechova K, Svecova L, Syrova Z, Stejskalova L, Blazkova J, Dvorak Z, Blahos J. Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene. Biochem Pharmacol. 2010 Jan 15;79(2):277-87 . doi: 10.1016/j.bcp.2009.08.017. Epub 2009 Aug 25.
10. Zhican Wang,1 Erin G. Schuetz,2 Yang Xu,1,3 and Kenneth E. Thummel; Interplay between Vitamin D and the Drug Metabolizing Enzyme CYP3A4; J Steroid Biochem Mol Biol. author manuscript; available in PMC 2014 Jul 1.
11. Blutt SE1, McDonnell TJ, Polek TC, Weigel NL. Calcitriol-induced apoptosis in LNCaP cells is blocked by overexpression of Bcl-2. Endocrinology. 2000 Jan;141(1):10-7.
12. Manju Daroach MD Tarun Narang MD; Correlation of vitamin D and vitamin D receptor expression in patients with alopecia areata: a clinical paradigm; international journal of dermatology; First published: December 15, 2017
13. Janegova A, Janega P1, Rychly B, Kuracinova K, Babal P. The role of Epstein-Barr virus infection in the development of autoimmune thyroid diseases. Endokrynol Pol. 2015;66(2):132-6. doi: 10.5603/EP.2015.0020.
14. Naviaux, RK, Metabolic Features of the Cell Danger Response; Mitochondrion Vol. 16 Pg 7-17
15. Michiyasu Ishizawa, Manabu Matsunawa; Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia; Journal of lipid research: annual 7, 2008, doi: 10.1194/jlr.M700293-JLR200
16. Pols TWH1, Puchner T1, Korkmaz HI1, Vos M1, Soeters MR2, de Vries CJM1. Lithocholic acid controls adaptive immune responses by inhibition of Th1 activation through the Vitamin D receptor. PLoS One. 2017 May 11;12(5):e0176715. doi: 10.1371/journal.pone.0176715. eCollection 2017.
17. Duygu GEZEN-AK, Erdinç DURSUN, and Selma YILMAZER; The Effect of Vitamin D Treatment On Nerve Growth Factor (NGF) Release From Hippocampal Neurons; Noro Psikiyatr Ars. 2014 Jun; 51(2): 157–162.
18. Cui X1, Pertile R1, Liu P1, Eyles DW2. Vitamin D regulates tyrosine hydroxylase expression: N-cadherin a possible mediator. Neuroscience. 2015 Sep 24;304:90-100. doi: 10.1016/j.neuroscience.2015.07.048. Epub 2015 Jul 23.
19. Katharina Nimptsch, Elizabeth A. Platz, Walter C. Willett, and Edward Giovannucci; Association between plasma 25-OH vitamin D and testosterone levels in men; Clin Endocrinol (Oxf). 2012 Jul; 77(1): 106–112.
20. Coughlan CA1, Chotirmall SH, Renwick J, Hassan T, Low TB, Bergsson G, Eshwika A, Bennett K, Dunne K, Greene CM, Gunaratnam C, Kavanagh K, Logan PM, Murphy P, Reeves EP, McElvaney NG. The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis. Am J Respir Crit Care Med. 2012 Nov 15;186(10):999-1007. doi: 10.1164/rccm.201203-0478OC. Epub 2012 Aug 16.
21. Hany William Z. Hanna, Cristiano Rizzo, Radwa Marawan Abdel Halim, Hemmat Elewa El Haddad, Randa Salam, Hazem El-Sayed Abou-Youssef,Vitamin D status in Hashimoto's thyroiditis and its association with vitamin D receptor genetic variants,The Journal of Steroid Biochemistry and Molecular Biology,Volume 212,2021,105922,ISSN 0960-0760,https://doi.org/10.1016/j.jsbmb.2021.105922.