3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy') and methylphenidate are widely used psychoactive substances. MDMA primarily enhances serotonergic neurotransmission, and methylphenidate increases dopamine but has no serotonergic effects. Both drugs also increase norepinephrine, resulting in sympathomimetic properties. Here we studied the effects of MDMA and methylphenidate on 24-hour plasma steroid profiles. 16 healthy subjects (8 men, 8 women) were treated with single doses of MDMA (125 mg), methylphenidate (60 mg), MDMA + methylphenidate, and placebo on 4 separate days using a cross-over study design. Cortisol, cortisone, corticosterone, 11-dehydrocorticosterone, aldosterone, 11-deoxycorticosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, and testosterone were repeatedly measured up to 24 h using liquid chromatography-tandem mass spectroscopy. MDMA significantly increased the plasma concentrations of cortisol, corticosterone, 11-dehydrocorticosterone, and 11-deoxycorticosterone and also tended to moderately increase aldosterone levels compared with placebo. MDMA also increased the sum of cortisol + cortisone and the cortisol/cortisone ratio, consistent with an increase in glucocorticoid production. MDMA did not alter the levels of cortisone, DHEA, DHEAS, androstenedione, or testosterone. Methylphenidate did not affect any of the steroid concentrations, and it did not change the effects of MDMA on circulating steroids. In summary, the serotonin releaser MDMA has acute effects on circulating steroids. These effects are not observed after stimulation of the dopamine and norepinephrine systems with methylphenidate. The present findings support the view that serotonin rather than dopamine and norepinephrine mediates the acute pharmacologically induced stimulation of the hypothalamic-pituitary-adrenal axis in the absence of other stressors.

Several microarray studies of prostate cancer (PCa) samples have suggested altered expression of the “orphan” enzyme short-chain dehydrogenase/reductase DHRS7 (retSDR4, SDR34C1). However, the role of DHRS7 in PCa is largely unknown and the impact of DHRS7 modulation on cancer cell properties has not yet been studied. Here, we investigated DHRS7 expression in normal human prostate and PCa tissue samples at different tumor grade using tissue microarray and immunovisualization. Moreover, we characterized the effects of siRNA-mediated DHRS7 knockdown on the properties of three distinct human prostate cell lines. We found that DHRS7 protein expression decreases alongside tumor grade, as judged by the Gleason level, in PCa tissue samples. The siRNA-mediated knockdown of DHRS7 expression in the human PCa cell lines LNCaP, BPH1, and PC3 significantly increased cell proliferation in LNCaP cells as well as cell migration in all of the investigated cell lines. Furthermore, cell adhesion was decreased upon DHRS7 knockdown in all three cell lines. To begin to understand the mechanisms underlying the effects of DHRS7 depletion, we performed a microarray study with samples from LNCaP cells treated with DHRS7-specific siRNA. Several genes involved in cell proliferation and adhesion pathways were found to be altered in DHRS7-depleted LNCaP cells. Additionally, genes of the BRCA1/2 pathway and the epithelial to mesenchymal transition regulator E-cadherin were altered following DHRS7 knockdown. Based on these results, further research is needed to evaluate the potential role of DHRS7 as a tumor suppressor and whether its loss-of-function promotes PCa progression and metastasis.

In traditional medicine, the oleoresinous gum of Pistacia lentiscus var. chia, so-called mastic gum, has been used to treat multiple conditions such as coughs, sore throats, eczema, dyslipidemia, and diabetes. Mastic gum is rich in triterpenes, which have been postulated to exert antidiabetic effects and improve lipid metabolism. In fact, there is evidence of oleanonic acid, a constituent of mastic gum, acting as a peroxisome proliferator-activated receptor γ agonist, and mastic gum being antidiabetic in mice in vivo. Despite these findings, the exact antidiabetic mechanism of mastic gum remains unknown. Glucocorticoids play a key role in regulating glucose and fatty acid metabolism, and inhibition of 11β-hydroxysteroid dehydrogenase 1 that converts inactive cortisone to active cortisol has been proposed as a promising approach to combat metabolic disturbances including diabetes. In this study, a pharmacophore-based virtual screening was applied to filter a natural product database for possible 11β-hydroxysteroid dehydrogenase 1 inhibitors. The hit list analysis was especially focused on the triterpenoids present in Pistacia species. Multiple triterpenoids, such as masticadienonic acid and isomasticadienonic acid, main constituents of mastic gum, were identified. Indeed, masticadienonic acid and isomasticadienonic acid selectively inhibited 11β-hydroxysteroid dehydrogenase 1 over 11β-hydroxysteroid dehydrogenase 2 at low micromolar concentrations. These findings suggest that inhibition of 11β-hydroxysteroid dehydrogenase 1 contributes to the antidiabetic activity of mastic gum.

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