Disrupting Y-Box-Binding Protein 1 Function Using OSU-03012 Prevents Endometriosis Progression in In Vitro and In Vivo Models.

The objective of the present study was to test the ability of OSU-03012 (2-amino-N-[4-[5-phenanthren-2-yl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]acetamide), a novel and potent celecoxib-derivative, to impair endometriosis progression in in vitro and in vivo models based on its ability to indirectly block Y-box-binding protein 1 (YB-1) function. 12Z human endometriotic epithelial cells and sexually mature female C57BL/6J mice were treated with OSU-03012. Cellular proliferation was quantified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid assay. Expression of YB-1 and phosphorylated YB-1 in 12Z cells and endometriotic lesions was evaluated by Western blotting and immunohistochemistry (IHC). The IHC for proliferating cell nuclear antigen was performed. OSU-03012 treatment resulted in decreased YB-1 and its phosphorylated form in both in vitro and in vivo models. Endometriotic lesion size was significantly reduced in OSU-03012-treated mice (27.6 ± 4.0 mm3) compared to those from the control group (50.5 ± 6.9 mm3, P < .0001). A significant reduction in endometriotic epithelial cell proliferation was observed in endometriotic lesions exposed to OSU-03012 treatment ( P = .0346). In conclusion, targeting YB-1 via OSU-03012 showed a potent antiproliferative effect on endometriotic epithelial cells in vitro and in a mouse model of disease.

Evaluation of YB-1 levels in patients with endometriosis.

OBJECTIVE: The objective of this study is the evaluation of serum YB-1 levels in the diagnosis of endometriosis. STUDY DESIGN: Serum samples of 12 patients with histologically confirmed endometriosis and of 10 control patients were collected. Western blot analysis was used to assess serum YB-1 levels. Groups were compared with Student's t-test or, if not normally distributed, with the Mann-Whitney test. Sensitivity and specificity for the potential diagnostic performance of serum YB-1 were assessed by receiver operating characteristic (ROC) curves. RESULTS: Serum YB-1 levels were significantly higher in patients with endometriosis (=0.004). The area under the curve was 0.867 (95% confidence interval 0.714-1.019) with sensitivity and specificity of 83.3% and 70% respectively. CONCLUSIONS: Serum YB-1 levels in patients with endometriosis are significantly higher compared to control patients and may be used as a potential diagnostic biomarker for endometriosis.

Pituitary-adrenal and sympathetic nervous system responses to stress in women remitted from recurrent major depression.

OBJECTIVE: To better understand the changes in hypothalamus-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) function after remission of depression. We characterized these systems at baseline and in response to a psychosocial stressor in a cohort of women remitted from recurrent major depression as well as in never-depressed healthy female controls. METHODS: Baseline HPA function was measured via saliva cortisol sampling at 8 AM and 4 PM over 7 days as well as quantification of urinary overnight cortisol secretion. The HPA system response to a psychosocial stressor was assessed by measuring serum cortisol and adrenocorticotropic hormone (ACTH) levels and SNS reactivity by determining serum epinephrine (E) and norepinephrine (NE) concentrations as well as autonomic nervous system changes by analysis of heart rate variability (HRV). The stressor included a speech task, mental arithmetic, and a cognitive challenge. RESULTS: In all, we studied 22 women remitted from recurrent major depression (age = 51.0 +/- 1.7 years) and 20 healthy controls (age = 54.2 +/- 1.6 years). Morning saliva cortisol concentrations were lower in remitted patients, paralleled by lower serum cortisol concentrations before stress testing. This group also displayed a blunted cortisol and ACTH response to the stressor, as compared with healthy controls. No between-group differences in HRV parameters were observed. CONCLUSION: In this group of women remitted from recurrent major depressive disorder, we found evidence of HPA system hypoactivity, both in the basal state and in response to a psychosocial stressor.

Effect of single-dose sertraline on the hypothalamus-pituitary-adrenal system, autonomic nervous system, and platelet function.

OBJECTIVE: Pharmacological treatment with selective serotonin reuptake inhibitors (SSRIs) is thought to decrease coronary risk in patients with depressive disorder. Selective serotonin reuptake inhibitor intake may (1) attenuate the hypothalamus-pituitary-adrenal (HPA) system, (2) improve disturbances of the autonomous nervous system, and (3) dampen the aggregability of platelets. There is only limited information about the influence of acute treatment with SSRIs on these systems, which is especially important for the initiation of therapy in high-risk cardiac patients. We compared the reaction of these systems to physical stress with single-dose SSRI treatment (100 mg) with that of placebo treatment. METHODS: Using a double-blind, crossover, placebo-controlled design, we assessed HPA system activity via serum cortisol and corticotropin as well as sympathetic nervous system by determining serum norepinephrine and epinephrine levels at baseline and as a response to stress. Analysis of heart rate variability (HRV) provided information on sympathetic/parasympathetic balance. Platelet activity was measured via flow-cytometric determination of platelet surface activation markers along with the serotonin (5-HT) uptake of platelets. RESULTS: We studied 12 healthy young men under placebo and verum conditions. We found higher HPA system activity at baseline and after physical activity under sertraline when compared with placebo, no difference in sympathetic nervous system activity after physical exertion and only slightly heightened baseline epinephrine values after sertraline intake. No difference was seen between sertraline and placebo intake regarding platelet activity and 5-HT uptake, HRV, blood pressure, and HR. CONCLUSIONS: Initiating sertraline treatment increases HPA system activity and epinephrine concentrations. We found no clinically relevant effect of single-dose sertraline treatment on autonomous nervous function, platelet activity, or platelet 5-HT uptake. These findings may not be extrapolated to patients with affective or cardiac disorders or to other SSRIs.