11β-hydroxysteroid Type Research Articles

The upregulation of 11β-HSD1 in ovarian granulosa cells by cortisol and interleukin-1β in polycystic ovary syndrome

Our previous study have demonstrated the elevated cortisol concentration in the follicular fluid (FF) contributed to the insulin resistance of the granulosa cells (GCs) in PCOS, but the complicated cortisol generation mechanisms are still unknown. 11β-hydroxysteroid type 1(11β-HSD1) mainly functions as reductase in intact cells, converting cortisone to cortisol. Cortisol and IL-1β are known to induce 11β-HSD1 in number of tissues, but few results were obtained in ovarian GCs In this study, FF and GCs from PCOS and non-PCOS patients were collected to study the interaction of cortisol and IL-1β in 11β-HSD1 expression. The ELISA and qRT-PCR revealed that the cortisol and IL-1β concentration in FF and 11β-HSD1 abundance in GCs were elevated in PCOS patients. By using cultured GCs in vitro, we demonstrated that both cortisol and IL-1β could stimulate 11β-HSD1 expression. The induction of 11β-HSD1 by IL-1β was further inducted by cortisol, whereas the induction of IL-1β and IL-6 expression by IL-1β was completely inhibited by cortisol. In conclusion, cortisol and IL-1β preformed a synergistically upregulation of 11β-HSD1 expression in GCs, contributing to the accumulation of cortisol in FF of PCOS patients. This may lead to the metabolic disorders of the ovary.

Thiazolo[3,2-a]pyrimidin-5-one derivatives as a novel class of 11β-hydroxysteroid dehydrogenase inhibitors

11β-hydroxysteroid type 1 dehydrogenase (11β-HSD1) is an enzyme that increases tissue concentrations of cortisol. Selective inhibitors of this enzyme regulate the level of cortisol and thus play a key role in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes.In this study the inhibitory activity of 29 thiazolo[3,2-a]pyrimidin-5-one derivatives on 11β-HSD1 were investigated. Studies were carried out with pooled human liver microsomes. A lot of analyzed compounds show activity for inhibiting 11β-HSD1 (up to 59.15% at concentration 10 µmol/l). Molecular docking simulation show that the molecule of the most active compound: 7-(cyclohexylmethyl)-2-iodomethyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-one forms hydrogen bonds with Ala172, Leu171, Leu215 or Tyr177. In addition, the cycloalkane moiety can create the hydrophobic contacts with NADP+. For this compound also the most favourable Docking Score value was obtained.The most active compound only in the slight degree inhibits 11β-HSD2 activity and is a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1. Consequently it can have a real effect on the regulation of the cortisol level in the body.

11-β hydroxysteroid type 1 knockout mice display an antidepressant-like phenotype in the forced swim test.

11β-dehydroxysteroid dehydrogenase (HSD) types 1 and 2, enzymes are involved in the activation and inactivation of glucocorticoids in vivo, respectively. Indirect evidence implicates two enzymes in the aetiology of depression but no study has directly assessed the potential role of 11 β-HSD1 in animal tests. We assessed 11 β-HSD1 knockout mice in the forced swim test (FST), tail suspension test (TST) and for locomotor activity. Genetic ablation of the 11β-HSD1 gene results in an antidepressant-like phenotype in the FST; the most widely utilised animal test of antidepressant activity, but not in the related TST. This may be related to the different biological substrates underlying these tests. The decreased FST immobility was not due to alterations in general activity. Taken together these results suggest that 11β-HSD1 may play an important role in depression-related behaviours and further studies are necessary to fully characterise its role in such behaviour.