activation pathways
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- MeSH
- lidé MeSH
- mapování mozku MeSH
- mozek MeSH
- nervové dráhy MeSH
- nervový systém MeSH
- Check Tag
- lidé MeSH
In higher metazoans, the nuclear hormone receptors activate transcription trough their specific adaptors, nuclear hormone receptor adaptors NCoA, which are absent in lower metazoans. The Nine amino acid TransActivation Domain, 9aaTAD, was reported for a large number of the transcription activators that recruit general mediators of transcription. In this study, we demonstrated that the 9aaTAD from NHR-49 receptor of nematode C.elegans activates transcription as a small peptide. We showed that the ancient 9aaTAD domains are conserved in the nuclear hormone receptors including human HNF4, RARa, VDR and PPARg. Also their small 9aaTAD peptides effectively activated transcription in absence of the NCoA adaptors. We also showed that adjacent H11 domains in ancient and modern hormone receptors have an inhibitory effect on their 9aaTAD function.
- MeSH
- aktivace transkripce * MeSH
- alfa receptor kyseliny retinové chemie metabolismus MeSH
- Caenorhabditis elegans chemie metabolismus MeSH
- hepatocytární jaderný faktor 4 chemie metabolismus MeSH
- lidé MeSH
- molekulární modely MeSH
- peptidy chemie metabolismus MeSH
- PPAR gama chemie metabolismus MeSH
- proteinové domény MeSH
- proteiny Caenorhabditis elegans chemie metabolismus MeSH
- receptory cytoplazmatické a nukleární chemie metabolismus MeSH
- receptory kalcitriolu chemie metabolismus MeSH
- sekvence aminokyselin MeSH
- sekvenční seřazení MeSH
- signální transdukce MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Signal transducer and activator of transcription 3 (STAT3) is phosphorylated by various kinases, several of which have been implicated in aberrant fibroblast activation in fibrotic diseases including systemic sclerosis (SSc). Here we show that profibrotic signals converge on STAT3 and that STAT3 may be an important molecular checkpoint for tissue fibrosis. STAT3 signaling is hyperactivated in SSc in a TGFβ-dependent manner. Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK, SRC, c-ABL, and JNK kinases. STAT3-deficient fibroblasts are less sensitive to the pro-fibrotic effects of TGFβ. Fibroblast-specific knockout of STAT3, or its pharmacological inhibition, ameliorate skin fibrosis in experimental mouse models. STAT3 thus integrates several profibrotic signals and might be a core mediator of fibrosis. Considering that several STAT3 inhibitors are currently tested in clinical trials, STAT3 might be a candidate for molecular targeted therapies of SSc.
- MeSH
- aktivace enzymů MeSH
- benzensulfonáty chemie MeSH
- biopsie MeSH
- bleomycin chemie MeSH
- dospělí MeSH
- fibroblasty metabolismus MeSH
- fibróza metabolismus MeSH
- fosforylace MeSH
- kolagen chemie MeSH
- konfokální mikroskopie MeSH
- kůže metabolismus MeSH
- kyseliny aminosalicylové chemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- myši MeSH
- receptory transformujícího růstového faktoru beta metabolismus MeSH
- senioři MeSH
- signální transdukce fyziologie MeSH
- systémová sklerodermie metabolismus MeSH
- transformující růstový faktor beta metabolismus MeSH
- transkripční faktor STAT3 metabolismus MeSH
- zánět MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- myši MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cyanobacterial toxin cylindrospermopsin (CYN) is an emerging freshwater contaminant, whose expanding environmental occurrence might result into increased human health risks. CYN is potent hepatotoxin, with cytotoxicity and genotoxicity documented in primary hepatocytes or hepatoma cell lines. However, there is only limited information about CYN effects on adult human liver stem cells (LSCs), which play an important role in liver tissue development, regeneration and repair. In our study with human liver cell line HL1-hT1 which expresses characteristics of LSCs, CYN was found to be cytotoxic and increasing cell death after 24-48 h exposure to concentrations >1 μM. Subcytotoxic 1 μM concentration did not induce cell death or membrane damage, but inhibited cellular processes related to energy production, leading to a growth stagnation after >72 h. Interestingly, these effects were not associated with increased DNA damage, reactive oxygen species production, or endoplasmic reticulum stress. However, CYN induced a sustained (24-48 h) activation of mitogen-activated protein kinases ERK1/2 and p38, and increased expression of stress-related transcription factor ATF3. Thus, LSCs were not primarily affected by CYN-induced genotoxicity and oxidative stress, but via activation of signaling and transcriptional pathways critical for regulation of cell proliferation, stress responses, cell survival and inflammation. Alterations of LSCs during CYN-induced liver injury, including the role of nongenotoxic mechanisms, should be therefore considered in mechanistic assessments of chronic CYN hepatotoxicity and hepatocarcinogenicity.
- MeSH
- bakteriální toxiny toxicita MeSH
- buněčné linie MeSH
- hepatocyty účinky léků MeSH
- játra metabolismus MeSH
- kmenové buňky MeSH
- lidé MeSH
- MAP kinasový signální systém MeSH
- mikrocystiny MeSH
- mitogenem aktivovaná proteinkinasa 1 metabolismus MeSH
- mitogenem aktivovaná proteinkinasa 3 metabolismus MeSH
- mitogenem aktivované proteinkinasy p38 metabolismus MeSH
- mořské toxiny MeSH
- oxidační stres účinky léků MeSH
- poškození DNA MeSH
- proliferace buněk MeSH
- reaktivní formy kyslíku metabolismus MeSH
- testy toxicity MeSH
- uracil analogy a deriváty toxicita MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
CD200/CD200R are highly conserved type I paired membrane glycoproteins that belong to the Ig superfamily containing a two immunoglobulin‑like domain (V, C). CD200 is broadly distributed in a variety of cell types, whereas CD200R is primarily expressed in myeloid and lymphoid cells. They fulfill multiple functions in regulating inflammation. The interaction between CD200/CD200R results in activation of the intracellular inhibitory pathway with RasGAP recruitment and thus contributes to effector cell inhibition. It was confirmed that the CD200R activation stimulates the differentiation of T cells to the Treg subset, upregulates indoleamine 2,3‑dioxygenase activity, modulates cytokine environment from a Th1 to a Th2 pattern, and facilitates an antiinflammatory IL‑10 and TGF‑β synthesis. CD200/CD200R are required for maintaining self‑tolerance. Many studies have demonstrated the importance of CD200 in controlling autoimmunity, inflammation, the development and spread of cancer, hypersensitivity, and spontaneous fetal loss.
- MeSH
- antigeny povrchové fyziologie MeSH
- CD antigeny fyziologie MeSH
- imunita fyziologie MeSH
- lidé MeSH
- receptory buněčného povrchu fyziologie MeSH
- signální transdukce MeSH
- zánět patofyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Scintigrafie slzných cest je vyšetřovací metoda, která nás informuje o funkci odvodného slzného systému. Autoři vyšetřili oboustranně scintigraficky 32 pa- cientů s obstrukcí nebo stenózou slzných cest, 22krát současně provedli kontrast- ní vyšetření slzných cest. U 7 suprasakálních a 5 sakálních obstrukcí a stenóz neprokázali v žádném případě průnik aktivity ze spojivkového vaku do slzných cest. U 16 subasakálních obstrukcí byl 12krát prokázán průnik aktivity do slzného vaku. U 5 pacientů s částečně zachovalou průchodností slzných cest byla 3krát prokázána aktivita v slzném vaku a jen 1krát byl prokázán obleněný průnik aktivity do dutiny nosní. U úplných obstrukcí a těžkých stenóz nám nepodává SSC oproti závěrům ostat- ních vyšetření (fluoresceinové testy, průplach, sondáž, kontrastní dakryocysto- grafie) nové informace o charakteru obstrukce. Metoda se uplatňuje především u stavů se zachovalou průchodností slzných cest, při vyšetřování velmi lehkých stenóz, intermitentním slzení a sporných stavů. Scintigrafie slzných cest je meto- dou doplňkovou, kterou je třeba hodnotit v souvislosti s ostatními metodami, zvláště metodami informujícími o anatomii slzného systému (dakryografie).
Scintigraphy of the lacrimal pathways is an examination method which informs us on the function of the efferent lacrimal system. The authors made bilateral scintigraphic examinations in 32 patients with obstruction or stenosis of the lacrimal pathways, 22 times they made concurrent contrast examinations of the lacrimal pathways. In seven suprasaccal and 5 saccal obstructions and stenoses they did not find penetration of activity from the conjunctival sac into the lacrimal pathways. In 16 subsaccal obstructions, 12 times penetration of activity into the lacrimal sac was found. In five patients with a partly preserved patency of the lacrimal pathways three times activity was detected in the lacrimal sac and in one instance slow penetration of activity into the nasal cavity. In complete obstructions and severe stenoses scintigraphy does not provide, as compared with conclusions of other examinations (fluorescein tests, irrigation, probing, contrast dacryocystography) new information on the type of obstruction. The method is useful in particular in conditions with a preserved patency of the lacrimal pathways, in examinations of very mild stenoses, intermittent lacrima- tion and doubtful cases. Scintigraphy of the lacrimal pathways is a supplementary method which must be evaluated in the context with other methods, in particular methods which provide information on the anatomy of the lacrimal system (dacryography).
