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Vitamny rozpustn v tucch

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Nuklern receptor:

(a)Typick NR m nkolik funknch domn. Variabiln NH2-terminln oblast obsahujetransaktivan domnu AF-1 nezvislou na ligandu. Konzervovan DBD je odpovdn za

rozpoznn specifick sekvence DNA. Variabiln spojujc oblast spojuje konzervovanou DBD s

LBD a je plochou pro dimerizaci. Na ligandu nezvisl aktivan transkripn domna je v NH2-

terminln oblasti, na ligandu zvisl AF-2 transaktivan domna je v COOH-terminln sti

LBD.

(b) NRs mohou aktivovat transkripci jako monomery nebo dimery (homodimery nebo

heterodimery s RXR. COUP, chicken ovalbumin upstream promoter; ERR, estrogen receptor-

related receptor HNF, hepatocyte nuclear factor; SF-1, steroidogenic factor 1.

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Superrodina nuklernchreceptor

Spolen struktura:

DNA vazn domna (DBD)

vazn domna specifick pro ligand (LBD-AP-2))

Vazn domna nespecifick pro ligand (AP-1)

Typy nuklrnch receptor1. steroidn

2. nesteroidn (RXR heterodimer)

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Signln transdukce

Ligandy jsou hydrofilnnebo hydrofobn

Receptor: povrchov nebo intracelulrn

lipofiln hormon-ve se na intracelulrn receptor-jdro-DNAa reguluje expresi

hydrofiln liganda-povrchov receptor

1.kinzov signln cesta-kinza vstupuje do jdra (MAPK)

2.kinzov cesta-uvolnn inhibinho proteinu-transkripn

faktor vstupuje do jdra (NF- B) 3.kinza-transkripn nebo regulan faktor vstupuje do

jdra (JAK-STAT a Smad).

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Role peroxisome proliferator-activated receptor (PPARs) vochran cvn stny

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Mechanismy transkripn regulacePPAR

Vechny 3 PPAR isotypy ( , a / , tak znm jako nebo ) obsahuj 5konzervovan domny. Jakoodpovd na rozpoznan ligand dochz ke konformanzmn v aktivan funkn domn 2 (AF2), co

podporuje povoln koaktivtor a uvolnn korepresor. Transkripce PPAR vyaduje tvorbu heterodimer s RXR.Aktivovan komplex RXR-PPAR vstupuje do interakce sespecifickmi PPREs (direct repeat 1) v pormotorechpozitivn regulovanch clovch gen. Mechanismusreprese clovch gen je mn jasn.

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Vitamin A

Absorbce vyadujeptomnost solluovch kyselin

Teratogenn vlastnosti- Isotretinoin

Antikancerogenn efekty-snad jako antioxidans sniuje tvorbuvolnch radikl a me tak omezovat niiv vliv kancerogen naDNA.

Skvamzn metaplazie v respiranm traktu pi deficitu vitaminu A

Ovlivuje senzitivitu na svtlo

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Vitamin A

Vitamin A (retinol) a jeho biologicky aktivn derivty(retinoidy), pedevm kyselina retinov (RA) majpleiotropninky na:

vvoj

bunnou proliferaci, diferenciaci a apoptzu

homeostzu

vidn reprodukci

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Retinoids absorbed from food are converted to retinol and bound to CRBP in the

intestine. Then, retinol is converted to retinyl esters and enters into bloodcirculation. The liver up takes retinyl esters, which are converted to retinol-RBPcomplex in the hepatocyte.

In the serum, the retinol-RBP complex is bound to transthyretin (TTR) in a 1:1 ratioto prevent elimination by the kidney and to ensure retinol is delivered to thetarget cell.

The uptake of retinol by the target cell is mediated by a trans-membraneprotein named stimulated by retinoic acid 6 (STRA6), which is a RBP receptor.

In the target cell, retinol either binds to CRBP or is oxidized to retinaldehyde byretinol dehydrogenase (RDH) in a reversible reaction. Then, retinaldehyde canbe oxidized by retinaldehyde dehydrogenase (RALDH) to RA.

In the target cell, RA either binds to CRABP or enters the nucleus and binds tonuclear receptors to regulate gene transcription.

Alternatively, RA can mediate via nongenomic mechanism and regulate

cellular function. Hepatocytes not only process retinoids, but also are the target cells. In addition,

hepatocytes located next to the storage site (stellate cell). Thus, retinoid-mediated signaling must have a profound effect in regulating hepatocytefunction and phenotype.

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Ligandy pro RA

RA psobprostednictvm: RAR (izoformy , a )

RXR (izoformy , a )

RAR:RXR heterodimery

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Mechanismy akce RXR

Mechanismy:

1. Ligandy jsou rzn, ne nutn endokrinn,

mohou bt intracelulrn 2. Mohou existovat i nkter cesty nezvisl

na ligand(fosforylankontrola) 3. Spoluprce s jinmi faktory, jako je AP-1

Model aktivace: neligovan receptor seve na DNA a vytv komplex skorepresorem-ligand se ve na DNA auvoluje korepresor-interakce s koaktivtory

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RXR a jeho promiskuitn

partnei v nuklernreceptorov funkci

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Extracelulrnvazn proteiny

RBP- retinol binding protein-retinol je ve vazb sekretovn

jtry. RBP produkovn jtry atukovou tkn.

retinol-RBP-TTR (transthyretin)

complex : cirkulace v krvi (zkrozmez)

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Intracelulrnvazn proteiny

CRBPs- cellular retinol bindingproteins- CRBPI- cytoplasmamnohch typbunk

CRBPII- cytoplasma stevnchbunk

CRABPs- cellular retinoic acid

binding proteins- semenn vky,vas deferens, ke, oko

CRABPII-ke

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Transkripn regulace proliferace

a diferenciace adipocyt

SREBP-1c-Sterol Regulatory Element Binding Protein

FOXC2 - forkhead transcription factor

C/EBP- CAAAT/enhancer binding protein-beta

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Deficit vitaminu A:

akn

zastaven rstu mlat vetnskeletlnho

selhn reprodukce, spjat zejmnas atrofi germinlnho epitelu varlat ankdy s peruenm enskho

sexulnho cyklu keratinizace rohovky s nslednou

slepotou

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Deficit vitaminu A

primrn defekt ve funkci Th bunk. Podkladem tohotodefektu je zejm nadprodukce IFN-. Retinoidy zejm

psob a na efektorov stadium aktivace T-bunk. modulace syntzy imunoglobulin prostednictvm RA se

zejm uskuteuje tak pmm efektem na B-buky.Tento efekt zvyujc syntzu Ig je zejm modulovn,alespo sten, autokrinnmi nebo parakrinnmi efekty

IL-6 na diferenciaci B-bunk.

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Rhodopsinovstnicovvizuln cyklusv tyince, kterukazuje dekompozicirhodopsinu bhemsvteln expozicea nslednou pomalou

novotvorburhodopsinuchemickmiprocesy

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Tvorba hyperpolarizanho

receptorovho potenciluzpsobenho dekompozicrhodopsinu

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inky vitaminu A a E

- karoten, vitamin A a vitamin Ezejm redukuj:

stn prekancerzy prekancerzy dlonho pku,

ke a plic

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Clov geny pro vitamin D

Gen Transkripce

Receptor pro vitamin D (VDR) zven

Proteiny vc Ca (kalbindiny) zven

Kalciov pumpa zven

Osteokalcin zven

Alkalick fosfatza zven

24-hydroxylza zven

PTH snen

1-hydroxylza snenKolagen snen

Interleukin-2 snen

Interferon snen

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RAR a VDR

vou se preferenn s nuklernmfaktorem pro 9-cis RA, kter se oznaujejako RXRretinoidn X receptor

RAR-VDR heterodimery. Oba typy vstupuj do interakce se leny

stejnch td koaktivtor, korepresor akointegrtor (proteiny). Tyto molekulrn

mechanismy umoujinterakce RAR a VDR,zaloen na alosterickch interakcchprotein-protein.

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Vitamin E

je schopen efektivn inhibovatcytokiny indukovan NFB. Ten hrajeklovou roli nap. pi indukci iNOSprostednictvmlipopolysacharid.

Familial vitamin E deficiency (AVED)zpsobuje ataxii a perifern neuropatii,

kter se podob Friedreichov ataxii.Byly u n objeveny 3 mutace v alfa-tokoferol transfer protein (TTP) genu (2zvanjbyly typu frame-shift).

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Vitamin E a K

U ostatnch vitaminrozpustnch v tucch (K a E)

nejsou interakce s nuklernmireceptory znmy, ale jejichstruktura tuto monost

nevyluuje. Vitamin E psobpes transkripn faktory, jako jeAP-1.

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Aktivace makrofg a bunk typu NK vitaminem E

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Deficit vitaminu E a kvalitaimunitn odpovdi u lovka

Imunitn odpov Vsledek

Mitogeneza T bunk Snen

Produkce IL-2 Snen

Fagocytza PMN Snen

Chemotaxe PMN Snen

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Oxidan stres

Je definovn jako nerovnovha mezi oxidanty aantioxidanty ve prospch oxidant, kter potencilnvede k pokozen buky nebo jejch struktur.

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Oxidan stres

je spjat se zmenenm potuantioxidanch molekul, jako alfa-tokoferol.

Alfa-tokoferol specificky sniuje proliferaci bunkhladk svaloviny cv v zvislostina koncentraci. Sniujepitom aktivitu protein kinzy C zvenm aktivity proteinfosfatzy 2A1, kter defosforyluje PKC-alfa, co vede ke zmnm sloena vazbytranskripnho faktoru pro AP-1 na DNA.

nkolikgen v bukch hladk svaloviny cv mn svou transkripci pod vlivemalfa-tokoferolu. Zvyuje se transkripce i translace alfa-tropomyosinu, ale jen podvlivem alfa-tokoferolu, nikoliv beta-tokoferolu

PKC-alfa se v prbhuivotazvyuje 8x, podobn jako MMP-1, kter degradujekolagen. Alfa-tokoferol sniuje expresi MMP, aniovlivuje aktivitu TIMP-1.

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Signalizace oxidanho stresu. Cytokiny a ROS indukuj aktivaci NF-B.Tato aktivace zabrauje apoptze bunk navozovan TNF upregulacantiapoptotickch gen

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Oxidan stres

nezvisle na doprovodnch promnnch, jako jetkov reakce, moduluje expresi gen prokolagen in vivo.

Rovnovha v oxidanm-antioxidanm stavu je

dleitou determinantou pro funkci imunocyt. Zajiuje: udrovn integrity a funknho stavu

membrnovch lipid, celulrnch protein a NK

kontrolu signln transdukce bunk imunitnhosystmu kontrolu genov exprese bunk imunitnho

systmu

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Antioxidan obrann systm

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Mon msta psoben antioxidant.

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K udren imunitnch funkc v prbhu celho ivota jepoteba optimlnho mnostvantioxidant.

S vkem stoup: produkce volnch kyslkovch radikl

peroxidace lipid

Pirozenmi antioxidanty jsou

vitamin E -karoten

glutathion.

Rovnovha oxidant a antioxidant

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Absorbce, modifikace, distribuce a inky molekul s antioxidanmiinky in vitro

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Kouen a antioxidan potencil

Kuci maj obvykle nzk pjemnutrinchantioxidant.

U kuk byly nalezeny:

vyplasmatick hladiny TNF a IL-6 nezmnn hladiny vitaminu A a E ni hladina vitaminu C, akoliv pjem

vitaminu C se od nekukneli

zven je produkce protein akutn fze(alfa-1 kysel glykoprotein,ceruloplasmin, alfa-2 makroglobulin).

Glucocorticoid Receptor Signaling

2009

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RNA Pol II

SMAD

Signaling

Sin3

GR

TBP

SMAD3SMAD4

SMAD3 SMAD4

JNK

p38

ERK1/2

NFB

GC

GC

GR

GC

GR

GC

GR

GC

GR

GC

GR

GC

GR

GC

GR

GC

GR

GC

GR

GC

GR

GC

CEBP

CEBP

ARC

STAT5

TRAP GRIP1

NFB

TAFs

TFIIH

SRC

p21

(CIP1)

HDAC

HSP90

HSP90

UbC9

NCOR

TGF1

Inflammatory

Cytokines

nGRE

Gene

Expression

GRE

Histone

Deacetylation

TATA

Cell Cycle

Arrest

Cell Cycle

Progression

Dissociation of

GR Inhibitory

Complex

Dimerization

PPP

P

P

Active

TGFR1

SWI/SNF

Complex

2009

ProteinLounge.com

C

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Glukokortikoidy 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 bindsas a dimmer to the C-terminal domain, the HSP70 (Heat Shock Protein-70 KD), the p59immunophilin, FKBP52 and the small p23 phosphoprotein.

GRs are composed of several conserved structural elements, including a COOH-terminalligand-binding domain (which also contains residues required for dimmerization andhormone-dependent gene transactivation), a nearby hinge region containing nuclearlocalization 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 domainin a favourable conformation for ligand binding.

The Gucocorticoid hormone passes through the plasma membrane into the cytoplasmwhere 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 inhibitorycomplex, thus inducing a conformational change which results in unmasking of thereceptor nuclear localization signal. Upon activation, GR thereby translocates to thenucleus and binds as a dimmer to DNA through its central domain, which is structurally

characterized by a DNA binding motif. The stabilization and nuclear localization of GR isfacilitated by its sumoylation by SUMO1 (Small Ubiquitin Related Modifier-1). GRinteracts either with DNA by targeting specific nucleotide palindromic sequences termedGRE (Glucocorticoid Response Elements) or nGRE (Negative GRE).

Depending on the nature of the GRE, the overall process of GR binding can result inactivation or repression of genes containing GR-binding sites.

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Glukokortikoidy

Although the activity of the GR is often thought of simply in terms of directgene transactivation, considerable cross-talk also occurs between the GRand a cohort of molecules to mediate their function as transcriptionalregulators. GRs can interact with coactivator complexes including CBP(CREB-Binding Protein), p300, ACTR (Activator of Thyroid Hormone andRetinoid 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 dependentchromatin remodeling activities.

Acetylation of core histones alters nucleosomal packing to allow increasedaccess of transacting factors and components of the basal transcriptionalmachinery to the local DNA. All these complexes may act in concert torelieve chromatin-mediated gene repression, with the TRAP (ThyroidHormone Receptor Associated Protein)-GRIP (Glucocorticoid ReceptorInteracting Proteins)-ARC (Activated Recruited Cofactor) complex

functioning to recruit the core transcription machinery. The nuclear receptors can also interact with the corepressors NCoR (Nuclear

Receptor Corepressor) and SMRT (Silencing Mediator of Retinoid andThyroid Hormone Receptor) thus leading to the recruitment of the Sin3-HDAC (Histone Deacetylase) corepressor complex, possessing histonedeacetylase functions. This corepressor complex can thereby inhibit genetranscription by counteracting the actions of the coactivator complexescontaining histone acetyltransferase activities.

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Glukokortikoidy Alternatively, GR can also modulate the expression of genes through a GRE-independent mechanism,

which is mediated in part through proteinprotein interactions of GR with other sequence-specific DNA-binding factors or coactivators. The negative modulation of gene transcription operated by Glucocorticoidsoccurs through non genomic mechanisms (transrepression), mediated by inhibitory influences exerted byactivated GR on the functions of several transcription factors. Transrepression is due at least in part todirect, 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 manygenes involved in inflammatory diseases such as Asthma. On the other hand, Glucocorticoid-activated GRincreases DNA-binding activity of CEBP-Beta via post-translational mechanisms involving phosphorylationat Thr(235). GR can interact as a monomer, via direct protein-protein interactions, with transcriptionfactors such as NF-KappaB and Activator Protein-1, activated by cytokines and other pro-inflammatorystimuli. 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-mediatedactivation 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 promoterregion. 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 genesresponsible for NF-KappaB inhibition include the two recently discovered proteins GILZ (Glucocorticoid-Induced Leucine Zipper) and GITR (Glucocorticoid-Induced Tumor Necrosis Factor Receptor Family-RelatedGene), which play a crucial role in modulation of T-cell activation and apoptosis. GR can also cooperatewith transcription factors, including octamer transcription factors Oct1 and Oct2; CREB (cAMP ResponseElement Binding Protein), and STAT5 (Signal Transducers and Activators of Transcription-5), to activatetranscription. Competition for limiting co-activators of transcription is an important determinant of the fateof 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 betweenActivator Protein-1 and the GR. Similarly, overexpression of CBP or SRC1 reverses the transcriptionalantagonism between the GR and NF-KappaB.

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Glukokortikoidy Glucocorticoids downregulate cell proliferation by decreasing the expression of Cyclin-

D1 and the phosphorylation of Rb (Retinoblastoma) protein and by activatingp21(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).

The Glucocorticoid signaling interacts with other signaling pathways activated byvarious cytokines, thus regulating diverse biological processes through modulating theexpression of target genes.

GR represses TGF- transcriptional activation of the PAI-1 (Plasminogen ActivatorInhibitor-1) and other genes in a ligand-dependent manner. Glucocorticoids inhibit theTGF- -induced expression of ECM (Extracellular Matrix) proteins including Fibronectinand Collagen, and proteinase inhibitors such as tissue inhibitors of Metalloproteinase.

The MAPKs (Mitogen-Activated Protein Kinases) play a key role in inflammatory celltypes through transducing the response from proinflammatory cytokine receptors tothe transcriptional apparatus. MAPK subgroups such as JNK regulate activation of theAP-1 complex required for proinflammatory gene expression. The MAPK p38 subgroupregulates 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 theGR exerts its antiinflammatory effects. The MAPK subgroups JNK, ERK1, ERK2, and p38are all targets of negative regulation by activated GRs.

Glucocorticoids destabilize the mRNA of the proinflammatory enzyme COX2(Cyclooxygenase-2) by inhibiting the activity of p38. The GR represses the MAPK familyby inhibiting the phosphorylation step required for their activation. The definedmolecular mechanism behind this inhibition has not been fully characterized and maybe cell type and stimulus specific.

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Glukokortikoidy

The therapeutic and prophylactic use of Glucocorticoids iswidespread due to their powerful anti-inflammatory,antiproliferative and immunomodulatory activity. These arewidely prescribed anti-inflammatory drugs, used to treat a widevariety of inflammatory diseases, including allergies, asthma,

rheumatoid arthritis, and auto-immune diseases. Glucocorticoidsenhance the production of other anti-inflammatory molecules suchas IL-1RA (Interleukin-1 Receptor Antagonist), IL-10 (Interleukin-10), secretory leukocyte inhibitory protein and neutralendopetidase (Ref.2).

The very effective control of airway inflammation exerted byGlucocorticoids in asthma is largely mediated by inhibition of thetranscriptional 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, cytoplasmicPLA2).

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Vitamin K

Vitamin K je vznamn pro regulaci krevnho sren a astnse v v regulaci kalcifikace mkkch tkn (CVN STNY).

Pirozen ve dvou formch: fylochinon a menachinon.Fylochinon (vitamin K1) je v zelen listov zelenin (brokolice,pent) v nkterch rostlinnch olejch. Menachinon (vitaminK2) jsou ivoinho a bakterilnho pvodu.

K3- pirozen metabolit Vitamin K2 je transkripnm regultorem gen specifickch

pro kost. Psob pes SXR (steroid and xenobiotic receptor)a tm podporuje expresi osteoblastickch marker. SXRfunguje jako xenobiotick senzor, ale zejm i jakomeditor kostn homeostzy.

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SXR a mechanismus psoben

Inoue KH a Inoue S: J Bone Miner Meat (2008) 26: 9-12

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SXR a vitamin K

Inoue KH a Inoue S: J Bone Miner Meat (2008) 26: 9-12

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Dky za pozornost