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D-vitamin szerepe a genetikai regulációban

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Az előadások a következő témára: "D-vitamin szerepe a genetikai regulációban"— Előadás másolata:

1 D-vitamin szerepe a genetikai regulációban
Prof. Dr. Szabó András egyetemi tanár, klinika-igazgató Semmelweis Egyetem II. sz Gyermekklinika, Budapest

2 D-vitamin szerepe a genetikai regulációban „To D or not to D…”
Prof. Dr. Szabó András egyetemi tanár Semmelweis Egyetem II. sz. Gyermekklinika DNN május 29.

3 A D vitamin hatásmechanizmusa a veleszületett immunitásban
Cathelcidin, Defensin Proposed mechanism for vitamin D’s action on the innate immune system. Vitamin D is produced in the skin upon exposure to UVB radiation from the sun or obtained from vitamin D containing foods. Vitamin D is converted to its major circulating form, 25-hydroxyvitamin D (25(OH)D), by the liver 25-hydroxylase and to 1,25-dihydroxyvitamin D (1,25(OH)2D) by the kidney 1-alpha-hydroxylase for optimal intestinal absorption of calcium in the classic vitamin D pathway. In the non-classic pathway of the immune system, the circulating 25(OH)D is taken up by macrophages, neutrophils or epithelial cells at locations exposed to the external environment. The 25(OH)D is converted to 1,25 (OH)2D in the target cell to act as an autocrine hormone. The locally produced 1,25(OH)2D binds to its nuclear receptor (VDR) and binds to the promoter of genes containing the vitamin D response element (VDRE). In neutrophils, macrophages and epithelial cells, this results in increased production of uncleaved cathelicidin (hCAP18 in humans) which undergoes further cleavage to the active cathelicidin (LL37 in humans) which results in killing of microorganisms. Of note, invading microorganisms that trigger specific toll-like receptors (in this example, TLR 2/1) result in increased production of the VDR and 1-alpha-hydroxylase which allows for vitamin D to enhance the production of cathelicidin only in the presence of adequate 25(OH)D substrate (adapted from Ref. [8]) J Mol Med (Berl) May; 88(5): 441–450.

4 Az 1,25(OH)2D3 szerepe az immunsejtekre (adaptív immunitás)
Overview of vitamin D and its interactions with cells of the immune system. Vitamin D3 intake is the combination of dietary consumption and UV exposure. After 25- hydroxylation of vitamin D3 in the liver, the serum 25OH-D3 value is a good indicator of the level of intake. The optimal value for serum 25OH-D3 remains a point of controversy. Hydroxylation of 25OH-D3 to 1,25OH-D3 occurs mainly in the kidney, but this step also occurs on peripheral cells, enabling rapid fine control of the activation of vitamin D in immune cells. Laboratory evidence suggests 1,25(OH)2-D3 can affect the function of a wide range of immunocytes, generally enhancing innate defense mechanisms and inhibiting inflammatory events. Journal of Allergy and Clinical Immunology Volume 131, Issue

5 A gének indukciója és repressziója
8 A gének indukciója és repressziója microRNS Histone acetyltransferase Histone deacetylase DNS metiláció

6 Vitamin D Receptor Signaling
26 25D3 Vitamin D Receptor Signaling -Pro-apoptosis -Anti-angiogenesis -Pro-differenciation -Anti-invasion -Anti-poliferation -Cell-cycle gátlás 125D3 125D3 VDR Actív Dimerization 125D3 125D3 SUMO1 VDR VDR UbC9 P CEBPb Cell Cycle Progression 125D3 125D3 VDR VDR CEBPa p21 (CIP1) Review: Our bones get more brittle with increasing age, and to add insult to injury, the most effective therapy for another problem that is associated with getting older, rheumatoid arthritis, often adds to the problem by causing bone resorption. The Glucocorticoid steroids, are the best available anti-inflammatories, and are used widely in the treatment of arthritis, as well as other inflammatory conditions such as dermatitis and autoimmune diseases. The Glucocorticoids, secreted by the Adrenal Cortex are powerful anti-inflammatory compounds due to their ability to inhibit all stages of the inflammatory response, from redness to wound healing to cell proliferation (Ref.1). They are powerful anti-inflammatory compounds that have the ability to inhibit all stages of the inflammatory response. They also have an essential role in cell metabolism and got the nomenclature, from their effect of raising the level of blood sugar (glucose) by stimulating gluconeogenesis in the liver: the conversion of fat and protein into intermediate metabolites that are ultimately converted into glucose. Cortisol (or Hydrocortisone) is the most important human Glucocorticoid. It is essential for life and regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Corticosterone, another Glucocorticoid, helps in the regulation of the conversion of amino acids into carbohydrates and glycogen by the liver, and stimulates glycogen formation in the tissues. All the cellular responses to Glucocorticoids is attributed to their binding to the intracellular GR (Glucocorticoid Receptor) (Ref.2), that, in turn, translocates to the nucleus, that positively and negatively modulates gene expression through diverse mechanisms. The GR is the Glucocorticoid-activated member of the nuclear receptor superfamily of transcription factors. It mediates the immunosuppressive and anti-inflammatory activity of these ligands in multiple physiological systems, including the respiratory and central nervous systems. Belonging to the family of steroid hormones, Glucocorticoids are essential for development and survival of vertebrates (Ref.3). Unbound GR is associated within the cytoplasm in an inactive oligomeric complex with some regulatory proteins such as the HSP90 (Heat Shock Protein-90 KD) which binds as a dimmer to the C-terminal domain, the HSP70 (Heat Shock Protein-70 KD), the p59 immunophilin, FKBP52 and the small p23 phosphoprotein. GRs are composed of several conserved structural elements, including a COOH-terminal ligand-binding domain (which also contains residues required for dimmerization and hormone-dependent gene transactivation), a nearby hinge region containing nuclear localization signals, a central zinc-finger-containing DNA-binding domain, and an NH2-terminal variable region important for ligand-independent gene transactivation. The interaction between HSP90 and GR is required to maintain the C-terminal domain in a favourable conformation for ligand binding (Ref.4). The Gucocorticoid hormone passes through the plasma membrane into the cytoplasm where it binds to the specific, high-affinity GR. The resulting complex is the non-DNA-binding oligomer of the GR in which the receptor is complexed with other proteins. Binding of hormone agonists releases GR from its interactions with the inhibitory complex, thus inducing a conformational change which results in unmasking of the receptor nuclear localization signal. Upon activation, GR thereby translocates to the nucleus and binds as a dimmer to DNA through its central domain, which is structurally characterized by a DNA binding motif (Ref.3). The stabilization and nuclear localization of GR is facilitated by its sumoylation by SUMO1 (Small Ubiquitin Related Modifier-1). The sumoylation process is catalyzed by the SUMO1-conjugating E2 enzyme Ubc9 (Ref.5). GR interacts either with DNA by targeting specific nucleotide palindromic sequences termed GRE (Glucocorticoid Response Elements) or nGRE (Negative GRE) (Ref.6). In particular, the dimeric GR places its two DNA-binding fragments into adjacent major grooves of the DNA double helix in correspondence of appropriately spaced GRE half palindromes. Depending on the nature of the GRE, the overall process of GR binding can result in activation or repression of genes containing GR-binding sites (Ref.3). Although the activity of the GR is often thought of simply in terms of direct gene transactivation, considerable cross-talk also occurs between the GR and a cohort of molecules to mediate their function as transcriptional regulators. GRs can interact with coactivator complexes including CBP (CREB-Binding Protein), p300, ACTR (Activator of Thyroid Hormone and Retinoid Receptors), SRC1 (Steroid Receptor Coactivator-1), and PCAF (p300/CBP Associated Factor) that possess HAT (Histone Acetyltransferase) activities, and the SWI/SNF complex which possesses ATP dependent chromatin remodeling activities (Ref.3 & 7). Acetylation of core histones alters nucleosomal packing to allow increased access of transacting factors and components of the basal transcriptional machinery to the local DNA. All these complexes may act in concert to relieve chromatin-mediated gene repression, with the TRAP (Thyroid Hormone Receptor Associated Protein)-GRIP (Glucocorticoid Receptor Interacting Proteins)-ARC (Activated Recruited Cofactor) complex functioning to recruit the core transcription machinery. The latter includes the TBP (TATA Box-Binding Protein), the TAFs (TBP Associated Factors), the general transcription factors TFIIA, TFIIB, TFIIE, TFIIF, TFIIH, and the enzyme, RNA Pol II (RNA Polymerase-II). The nuclear receptors can also interact with the corepressors NCoR (Nuclear Receptor Corepressor) and SMRT (Silencing Mediator of Retinoid and Thyroid Hormone Receptor) thus leading to the recruitment of the Sin3-HDAC (Histone Deacetylase) corepressor complex, possessing histone deacetylase functions. This corepressor complex can thereby inhibit gene transcription by counteracting the actions of the coactivator complexes containing histone acetyltransferase activities (Ref.2 & 8). Alternatively, GR can also modulate the expression of genes through a GRE-independent mechanism, which is mediated in part through protein–protein interactions of GR with other sequence-specific DNA-binding factors or coactivators (Ref.9). The negative modulation of gene transcription operated by Glucocorticoids occurs through non genomic mechanisms (transrepression), mediated by inhibitory influences exerted by activated GR on the functions of several transcription factors. This contributes to the anti-inflammatory properties of the Glucocorticoids. Transrepression is due at least in part to direct, physical interactions between monomeric GR and transcription factors such as c-Jun-c-Fos and NF-KappaB (Nuclear Factor-KappaB), that synergistically coordinate the transcriptional activation of many genes involved in inflammatory diseases such as Asthma (Ref.10). In particular, the three main domains of GR may contribute to interact with the p65 subunit of NF-KappaB and with both Jun and Fos components of Activator Protein-1. The resulting reciprocal antagonism of the transcription factors engaged in these protein-protein associations causes an impairment of their transcriptional properties. However, Activator Protein-1, consisting of c-Jun homodimmers can also enhance GRE-mediated transactivation. On the other hand, Glucocorticoid-activated GR increases DNA-binding activity of CEBP-Beta via post-translational mechanisms involving phosphorylation at Thr(235) (Ref.11). GR can interact as a monomer, via direct protein-protein interactions, with transcription factors such as NF-KappaB and Activator Protein-1, activated by cytokines and other pro-inflammatory stimuli (Ref.4). The resulting mutual repression prevents both GR and the other transcription factors from binding to their respective DNA response elements. In addition, Glucocorticoids repress NF-KappaB-mediated activation of pro-inflammatory genes by reducing the levels of serine-2 phosphorylation of the carboxy-terminal domain of RNA Pol II, which is essential for the recruitment of this enzyme to the promoter region. Glucocorticoids also increase the transcription and synthesis of I-KappaB and thus may inhibit NF-KappaB by promoting its retention in the cytosol. Other products of Glucocorticoid inducible genes responsible for NF-KappaB inhibition include the two recently discovered proteins GILZ (Glucocorticoid-Induced Leucine Zipper) and GITR (Glucocorticoid-Induced Tumor Necrosis Factor Receptor Family-Related Gene), which play a crucial role in modulation of T-cell activation and apoptosis. GR can also cooperate with transcription factors, including octamer transcription factors Oct1 and Oct2; CREB (cAMP Response Element Binding Protein), and STAT5 (Signal Transducers and Activators of Transcription-5), to activate transcription. Competition for limiting co-activators of transcription is an important determinant of the fate of the cross-talk between the GR and other transcription factors. Both Activating Protein-1 and the GR are co-activated by CBP-p300, and in fact overexpression of CBP or p300 reverses the antagonism between Activator Protein-1 and the GR. Similarly, overexpression of CBP or SRC1 reverses the transcriptional antagonism between the GR and NF-KappaB (Ref.8 & 12). Glucocorticoids downregulate cell proliferation by decreasing the expression of Cyclin-D1 and the phosphorylation of Rb (Retinoblastoma) protein and by activating p21(CIP1) (Cyclin Dependent Kinase Inhibitor-p21). The antiproliferative effect of Glucocorticoids is mediated by the GR and CEBP-Alpha, and both active transcription factors are required to induce the synthesis of p21(CIP1). In human cells, including lung fibroblasts, pulmonary and bronchial smooth-muscle cells, and peripheral-blood lymphocytes, the GR forms a complex with CEBP-Alpha, which then binds to the CCAAT DNA consensus sequence in the p21(CIP1) promoter (Ref.13). The Glucocorticoid signaling interacts with other signaling pathways activated by various cytokines, thus regulating diverse biological processes through modulating the expression of target genes. GR represses TGF-â transcriptional activation of the PAI-1 (Plasminogen Activator Inhibitor-1) and other genes in a ligand-dependent manner. Glucocorticoids inhibit the TGF-â-induced expression of ECM (Extracellular Matrix) proteins including Fibronectin and Collagen, and proteinase inhibitors such as tissue inhibitors of Metalloproteinase. GR inhibits transcriptional activation by both Smad3 and Smad4 C-terminal activation domains (Ref.14). The MAPKs (Mitogen-Activated Protein Kinases) play a key role in inflammatory cell types through transducing the response from proinflammatory cytokine receptors to the transcriptional apparatus. MAPK subgroups such as JNK regulate activation of the AP-1 complex required for proinflammatory gene expression. The MAPK p38 subgroup regulates the stability of mRNAs that encode the proinflammatory molecules TNF-Alpha, IL-6, IL-8, and VEGF (Vascular Endothelial Growth Factor). Negative regulation of the MAPK family by Glucocorticoids may be an additional mechanism by which the GR exerts its antiinflammatory effects (Ref.15). The MAPK subgroups JNK, ERK1, ERK2, and p38 are all targets of negative regulation by activated GRs. For example, Glucocorticoids destabilize the mRNA of the proinflammatory enzyme COX2 (Cyclooxygenase-2) by inhibiting the activity of p38 (Ref.16). The GR represses the MAPK family by inhibiting the phosphorylation step required for their activation. The defined molecular mechanism behind this inhibition has not been fully characterized and may be cell type and stimulus specific (Ref.9). The therapeutic and prophylactic use of Glucocorticoids is widespread due to their powerful anti-inflammatory, antiproliferative and immunomodulatory activity (Ref.17). These are widely prescribed anti-inflammatory drugs, used to treat a wide variety of inflammatory diseases, including allergies, asthma, rheumatoid arthritis, and auto-immune diseases. Glucocorticoids enhance the production of other anti-inflammatory molecules such as IL-1RA (Interleukin-1 Receptor Antagonist), IL-10 (Interleukin-10), secretory leukocyte inhibitory protein and neutral endopetidase (Ref.2). Glucocorticoids are important mediators of the immune system and modulate the biological activities of inflammatory cytokines. The very effective control of airway inflammation exerted by Glucocorticoids in asthma is largely mediated by inhibition of the transcriptional activity of several different genes encoding pro-inflammatory proteins such as cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-11, IL-13, TNF-Alpha, GMCSF, IFN-Gamma), chemokines (IL-8, RANTES, MIP-1a, MCP-1, MCP-3, MCP-4, Eotaxin), adhesion molecules (ICAM1, VCAM1, E-Selectin), and mediator-synthesizing enzymes (i-NOS, COX2, cytoplasmic PLA2) (Ref.9, 10 & 16). Glucocorticoids, acting through the GR, potently modulate immune function and are a mainstay of therapy for treatment of inflammatory conditions including allergies, asthma, rheumatoid arthritis; autoimmune diseases, leukemias and lymphomas (Ref.3). Common Glucocorticoids include prednisone, dexamethasone, and hydrocortisone. Hydrocortisone is used as an anti-inflammatory in the treatment of arthritis, as well as other inflammatory conditions such as dermatitis and autoimmune disease. While Glucocorticoids are widely used as drugs to treat various inflammatory conditions, prolonged Glucocorticoid use may have adverse side effects such as immunosuppression, fluid shifts, brain changes, and psychological changes. Physicians are therefore very cautious about prescribing these medications, especially for long periods of time. The search for novel Glucocorticoids with reduced side effects has been intensified by the discovery of new molecular details regarding the function of the Glucocorticoid receptor. These new insights may pave the way for novel, safer therapies that retain the efficacy of currently prescribed steroids (Ref.18 and 19). References: 1. Miller AH Depression and immunity: a role for T cells? Brain Behav Immun Jan;24(1):1-8. Epub 2009 Oct 8. PubMed ID: 2. De Iudicibus S, Franca R, Martelossi S, Ventura A, Decorti G. Molecular mechanism of glucocorticoid resistance in inflammatory bowel disease. World J Gastroenterol Mar 7;17(9): PubMed ID: 3. Marwick JA, Adcock IM, Chung KF. Overcoming reduced glucocorticoid sensitivity in airway disease: molecular mechanisms and therapeutic approaches. Drugs May 28;70(8): doi: / PubMed ID: 4. Davies TH, Ning YM, Sanchez ER. Differential control of Glucocorticoid receptor hormone-binding function by tetratricopeptide repeat (TPR) proteins and the immunosuppressive ligand FK506. lBiochemistry Feb 15;44(6): l PubMed ID: 5. Chrousos GP, Kino T. Intracellular glucocorticoid signaling: a formerly simple system turns stochastic. Sci STKE Oct 4;2005(304):pe48. PubMed ID: 6. Bhargava A, Pearce D. Mechanisms of mineralocorticoid action: determinants of receptor specificity and actions of regulated gene products. Trends Endocrinol Metab May-Jun;15(4): PubMed ID: 7. Ruegg J, Holsboer F, Turck C, Rein T. Cofilin 1 is revealed as an inhibitor of Glucocorticoid receptor by analysis of hormone-resistant cells. Mol Cell Biol Nov;24(21): PubMed ID: 8. Grenier J, Trousson A, Chauchereau A, Amazit L, Lamirand A, Leclerc P, Guiochon-Mantel A, Schumacher M, Massaad C. Selective recruitment of p160 coactivators on Glucocorticoid-regulated promoters in Schwann cells. Mol Endocrinol Dec;18(12): PubMed ID: 9. Schoneveld OJ, Gaemers IC, Lamers WH. Mechanisms of Glucocorticoid signalling. Biochim Biophys Acta Oct 21;1680(2): Review. PubMed ID: 10. Stellato C. Post-transcriptional and nongenomic effects of Glucocorticoids. Proc Am Thorac Soc. 2004;1(3): Review. PubMed ID: 11. Bladh LG, Liden J, Pazirandeh A, Rafter I, Dahlman-Wright K, Nilsson S, Okret S. Identification of target genes involved in the antiproliferative effect of Glucocorticoids reveals a role for nuclear factor-(kappa)B repression. Mol Endocrinol Mar;19(3): PubMed ID: 12. Berg T, Didon L, Barton J, Andersson O, Nord M. Glucocorticoids increase C/EBPbeta activity in the lung epithelium via phosphorylation. Biochem Biophys Res Commun Aug 26;334(2): PubMed ID: 13. Cascallana JL, Bravo A, Donet E, Leis H, Lara MF, Paramio JM, Jorcano JL, Perez P. Ectoderm-targeted overexpression of the Glucocorticoid receptor induces hypohidrotic ectodermal dysplasia. Endocrinology Jun;146(6): PubMed ID: 14. Roth M, Johnson PR, Borger P, Bihl MP, Rudiger JJ, King GG, Ge Q, Hostettler K, Burgess JK, Black JL, Tamm M. Dysfunctional interaction of C/EBPalpha and the Glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N Engl J Med Aug 5;351(6): PubMed ID: 15. Li G, Wang S, Gelehrter TD. Identification of Glucocorticoid receptor domains involved in transrepression of transforming growth factor-beta action. J Biol Chem Oct 24;278(43): PubMed ID: 16. Bruna A, Nicolas M, Munoz A, Kyriakis JM, Caelles C. Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by Glucocorticoids. EMBO J Nov 17;22(22): PubMed ID: 17. Brewer JA, Khor B, Vogt SK, Muglia LM, Fujiwara H, Haegele KE, Sleckman BP, Muglia LJ. T-cell glucocorticoid receptor is required to suppress COX-2-mediated lethal immune activation. Nat Med Aug 31 [Epub ahead of print] PubMed ID: 18. Miner JN, Hong MH, Negro-Vilar A. New and improved Glucocorticoid receptor ligands. Expert Opin Investig Drugs Dec;14(12): PubMed ID: 19. Rosen J, Miner JN. The search for safer Glucocorticoid receptor ligands. Endocr Rev May;26(3): PubMed ID: ARC SWI/SNF Complex HAT1 GRIP1 Cell Cycle Arrest CBP Acetylation Histone TRAP SRC PCAF Több mint 2700 gén szabályozása ismert 125D3 125D3 TAFs TFIIB H4 H3 Ac TFIIF TFIIA TBP RNA Pol II VDR VDR TFIIE TFIIH VDRE TATA Histone Deacetylation Sin3 Gene Expression NCOR HDAC Qiagen, modified by Szabó.A. 6

7 Az 1,25(OH)2D3 hatása az immunrendszer szabályozásában
Nature Reviews Immunology 8, (September 2008)

8 Effects of Vitamin D deficiency on inflammation and EPO-resistant anaemia.
(Bone Morphogenetic proteins) Nephrol. Dial. Transplant. First published online: March 6, 2013

9 D vitamin kezelés hatása az EPO szükségletre
n=126 5st. HD Vitamin D Treatment Period 1./ Induló érték, 2./ 4 x IU/ hét, 3./ 3 x IU / hó, 3. JNEPHROL 2011; 24(01):

10 Aktív D Vitamin = hormon nem vitamin
pre-vitamin D3 7,8-Dehydrocholesterol Bőr Vitamin D3* CYP2R1 (25-hydroxylase), VDBP Máj 25(OH) D3 nyáron > ug/l télen > 30 ug/l CYP24 (24,25-hydroxylase) Vese ng/l = 0,1% 1,25(OH)2 D3 Sunlight plays an important role in the metabolism of vitamin D. When you are exposed to sunlight, ultraviolet B rays from sunlight converts 7-dehydrocholesterol present on the skin to pre-vitamin D3 , which is further converted to (native) vitamin D3. Once in the blood circulation, vitamin D binds to the binding protein to reach the liver where it is converted to the inactive form, or 25-hydroxyvitamin D. 25-Hydroxyvitamin D gets converted to the active form 1,25-dihydroxyvitamin D in kidneys. The active form is also known as calcitriol and its renal production is controlled by phosphorus, calcium and fibroblast growth factor-23. The synthesis of calcitriol is controlled by a negative feedback mechanism involving decreased secretion of PTH by the parathyroid gland. Calcitriol also enhances intestinal absorption of calcium. Have a look at the schematic representation of vitamin D. 1(Holick MF. NEJM; 2007;357:269) Reference Holick MF. vitamin D deficiency. N Engl J Med. 2007;357:266–281. Aktív D Vitamin = hormon nem vitamin A receptor expressziót csökkenti: EBV infekció Gomba fertőzések, stb. VDR 10 10 10 Modified: Holick MF. NEJM. 2007;357: 10

11 Vitamin D Receptor koncentráció csökkenése
VDR receptor down-regulated by Mycobacterium tuberculosis Yongzhong, et al:”Using a cDNA microarray to study cellular gene expression altered by Mycobacterium tuberculosis.” Chin Medicine J 2003 Borrelia burgdorferi down regulates VDR expression 50-fold Salazar, et al: “Activation of human monocytes by Borrelia burgdorferi…” PLOSpathogens May 2009 Aspergillus fumigatus down regulates VDR expression in macrophages and airway epithelialcells Coughlan CA et al: „The effect os Asp.fumigans on VDR…” Am J Respir Crit Med 2012 Aug 16 Both live Borrelia and lysed organisms were used → VDR receptor expressions down regulated 50 fold by live Bb → VDR receptor expressions down regulated 8 fold by lysed Bb Salazar, et al: “Activation of human monocytes by Borrelia burgdorferi…” PLOSpathogens May 2009

12 Epstein Barr Virus hatása VDR expressiora
Yenamandra SP et al Exp Oncol ,2 Yenamandra SP et al: Experimental Oncology 31, 92–96, 2009

13 A VDR koncentráció szerepe az emlő carcinoma túlélésére
Alacsony IRS Magas IRS Pozitív kontroll Negatív kontroll (A, B) Immunohistochemical staining of vitamin D receptor (VDR) in human breast cancer. The illustrations show immunoreaction after incubation with the primary antibody of the cells of the malignant breast tumors (25× lens). (A) Negative/low immunoreactivity score (IRS) and (B) high IRS. (C, D) Placental tissue serves as negative and positive control for VDR. For negative controls (blue), isotype-matching control antibodies of the same species were used (C). Positive control (D) shows VDR staining of villous trophoblast cells. Bars = 100 µm. IRS= immunoreactivity score A Vitamin D receptor (VDR) immunohistochemiai festése emlő carcinomában J.Histochem Cytochem (2):

14 A DVR koncentráció szerepe az emlő carcinoma túlélésére (Kaplan-Meier)
IRS 0-4 v.6-12 IRS 0-4 v.6-12 IRS 0-1 v.2-3 Magas IRS OS PFS PFS Alacsony IRS IRS 0-1 v.2-3 IRS <50% v.>50% IRS <50% v.>50% (A) Progressive-free survival (PFS) shown in Kaplan-Meier curves of two different vitamin D receptor groups classified as negative and moderately positive (0–4 immunoreactivity score [IRS]) or highly positive IRS (6–12 IRS). (B) Overall survival (OS) shown in Kaplan-Meier curves of two different vitamin D receptor groups classified as negative and moderately positive (0–4 IRS) or highly positive (6–12 IRS). (C) PFS shown in Kaplan-Meier curves of two different vitamin D receptor groups for intensity of staining (0–1 vs 2–3). (D) OS shown in Kaplan-Meier curves of two different vitamin D receptor groups for intensity of staining (0–1 vs 2–3). (E) PFS shown in Kaplan-Meier curves of two different vitamin D receptor groups for percentage of cells staining positive (0%–50% vs 50%–100%). (F) OS shown in Kaplan-Meier curves of two different vitamin D receptor groups for percentage of cells staining positive (0%–50% vs 50%–100%). OS PFS OS IRS= immunoreactivity score PFS = Progressive-free, OS = Overall survival J.Histochem Cytochem (2):

15 DVR homológ up-reguláció
Humán Monocyta Monocyta (Mo) és makrofág (MAC) sejtkultúra * p<0,01 v. 0 óra * DVR fmol/mg protein MO 336±56* MO+1,25-D3 554±115** MAC ±32 MAC+1,25-D3 240±59** Adatok átlaga±SEM három kísérletből. * p<0,03 v.MAC,**p< 0,03 v. MO, (Mann-Whitney U-test) * 0,25ug 1,25(OH2D3 p.os kezelés Merke,Szabó et al.: Calcif Tissue Int 45(4): 255-6, 1989 Kreutz, Szabó; et al. Blood 82. (4): , 1993

16 25OHD3 szintek gyermekkorban
(1-18 éves, n = 3097) <10 ug/l ug/l ug/l >30 ug/l n=1772 n=1325 áprilistól - októberig novembertől - márciusig 5% = ca gyermek Gyermekklinika adatai

17 Köszönöm a figyelmet

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