The novel copper complex [Cu(phen)2(salubrinal)](ClO4)2 (C0SAL) has been synthesised and characterised. Copper(ii) is coordinated by salubrinal through the thionic group, as shown by the UV-Vis, IR, ESI-MS and tandem mass results, together with the theoretical calculations. The formed complex showed a DPPH radical scavenging ability higher than that of salubrinal alone. Studies on lipid oxidation inhibition showed that the C0SAL concentration, required to inhibit the enzyme, was lower than that of salubrinal. The inhibition of the enzyme could take place via allosteric modulation, as suggested by docking calculations. C0SAL showed a good cytotoxic activity on A2780 cells, 82 fold higher than that of the precursor salubrinal and 1.4 fold higher than that of [Cu(phen)2(H2O)](ClO4)2. Treatment with C0SAL in SKOV3 ovarian cancer cells induced expression of GRP-78 and DDIT3 regulators of ER-stress response. The cytotoxic effect of C0SAL was reverted in the presence of TUDCA, suggesting that C0SAL induces cell death through ER-stress. In A2780 cells treated with C0SAL γ-H2AX was accumulated, suggesting that DNA damage was also involved.

• MeSH
• antivirové látky farmakologie   MeSH
• cinnamáty farmakologie   MeSH
• fenantroliny farmakologie   MeSH
• kyselina taurochenodeoxycholová farmakologie   MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• měď farmakologie   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• peroxidace lipidů účinky léků   MeSH
• poškození DNA účinky léků   genetika   MeSH
• thiomočovina analogy a deriváty   farmakologie   MeSH
• transkripční faktor CHOP genetika   metabolismus   MeSH
• transmisní elektronová mikroskopie MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Ovarian surface epithelium (OSE) forms a single layer of mostly cuboidal cells on surface of mammalian ovaries that is inherently exposed to cell stress evoked by tissue damage every ovulation and declines morphologically after menopause. Endoplasmic reticulum (ER) is a principal cell organelle involved in proteosynthesis, but also integrating various stress signals. ER stress evokes a conserved signaling pathway, the unfolded protein response (UPR), leading to cell death or adaptation to stress conditions. In this work, we document that mouse OSE suffers from ER stress during replicative senescence in vitro, develops abnormalities in ER and initiates UPR. Attenuation of ER stress in senescent OSE by tauroursodeoxycholic acid (TUDCA) reconditions ER architecture and leads to delayed onset of senescence. In summary, we show for the first time a mutual molecular link between ER stress response and replicative senescence leading to phenotypic changes of non-malignant ovarian surface epithelium.

• MeSH
• down regulace účinky léků   MeSH
• epitel účinky léků   patologie   ultrastruktura   MeSH
• kyselina taurochenodeoxycholová farmakologie   MeSH
• messenger RNA genetika   metabolismus   MeSH
• myši MeSH
• ovarium patologie   MeSH
• stárnutí buněk účinky léků   MeSH
• stres endoplazmatického retikula účinky léků   MeSH
• tunikamycin farmakologie   MeSH
• upregulace účinky léků   MeSH
• zkracování telomer účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Stress of endoplasmic reticulum (ERS) is one of the molecular triggers of adipocyte dysfunction and chronic low inflammation accompanying obesity. ERS can be alleviated by chemical chaperones from the family of bile acids (BAs). Thus, two BAs currently used to treat cholestasis, ursodeoxycholic and tauroursodeoxycholic acid (UDCA and TUDCA), could potentially lessen adverse metabolic effects of obesity. Nevertheless, BAs effects on human adipose cells are mostly unknown. They could regulate gene expression through pathways different from their chaperone function, namely through activation of farnesoid X receptor (FXR) and TGR5, G-coupled receptor. Therefore, this study aimed to analyze effects of UDCA and TUDCA on human preadipocytes and differentiated adipocytes derived from paired samples of two distinct subcutaneous adipose tissue depots, abdominal and gluteal. While TUDCA did not alter proliferation of cells from either depot, UDCA exerted strong anti-proliferative effect. In differentiated adipocytes, acute exposition to neither TUDCA nor UDCA was able to reduce effect of ERS stressor tunicamycin. However, exposure of cells to UDCA during whole differentiation process decreased expression of ERS markers. At the same time however, UDCA profoundly inhibited adipogenic conversion of cells. UDCA abolished expression of PPARγ and lipogenic enzymes already in the early phases of adipogenesis. This anti-adipogenic effect of UDCA was not dependent on FXR or TGR5 activation, but could be related to ability of UDCA to sustain the activation of ERK1/2 previously linked with PPARγ inactivation. Finally, neither BAs did lower expression of chemokines inducible by TLR4 pathway, when UDCA enhanced their expression in gluteal adipocytes. Therefore while TUDCA has neutral effect on human preadipocytes and adipocytes, the therapeutic use of UDCA different from treating cholestatic diseases should be considered with caution because UDCA alters functions of human adipose cells.

• MeSH
• adipogeneze účinky léků   MeSH
• aktivace enzymů účinky léků   MeSH
• buněčná diferenciace účinky léků   MeSH
• cytokiny genetika   MeSH
• kyselina taurochenodeoxycholová farmakologie   MeSH
• kyselina ursodeoxycholová farmakologie   MeSH
• lidé MeSH
• mitogenem aktivovaná proteinkinasa 1 metabolismus   MeSH
• mitogenem aktivovaná proteinkinasa 3 metabolismus   MeSH
• podkožní tuk cytologie   MeSH
• proliferace buněk účinky léků   MeSH
• regulace genové exprese účinky léků   MeSH
• stres endoplazmatického retikula účinky léků   MeSH
• tukové buňky cytologie   účinky léků   metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH