Nuclear Factor of Activated T Cells-dependent Down-regulation of the Transcription Factor Glioma-associated Protein 1 (GLI1) Underlies the Growth Inhibitory Properties of Arachidonic Acid

Numerous reports have demonstrated a tumor inhibitory effect of polyunsaturated fatty acids (PUFAs). However, the molecular mechanisms modulating this phenomenon are in part poorly understood. Here, we provide evidence of a novel antitumoral mechanism of the PUFA arachidonic acid (AA). In vivo and in vitro experiments showed that AA treatment decreased tumor growth and metastasis, and increased apoptosis. Molecular analysis of this effect showed significantly reduced expression of a subset of antiapoptotic proteins, including BCL2, BFL1/A1 and 4-1BB, in AA-treated cells. We demonstrated that downregulation of the transcription factor GLI1 in AA-treated cells is the underlying mechanism controlling BCL2, BFL1/A1 and 4-1BB expression. Using luciferase reporters, chromatin immunoprecipitation, and expression studies, we found that GLI1 binds to the promoter of these antiapoptotic molecules, and regulates their expression and promoter activity. We provide evidence that AA-induced apoptosis and downregulation of antiapoptotic genes can be inhibited by overexpressing GLI1 in AA-sensitive cells. Conversely, inhibition of GLI1 mimics AA treatments, leading to decreased tumor growth, cell viability and expression of antiapoptotic molecules. Further characterization showed that AA represses GLI1 expression by stimulating NFATc1 nuclear translocation, which then binds the GLI1 promoter and represses its transcription. AA was shown to increase reactive oxygen species. Treatment with antioxidants reduced the AA-induced apoptosis, downregulation of GLI1 and NFATc1 activation, indicating that NFATc1 activation and GLI1 repression require the generation of reactive oxygen species. Collectively, these results define a novel mechanism underlying AA antitumoral functions that may serve as a foundation for the future PUFA-based therapeutic approaches

The Transcription Factor GLI1 Mediates TGFb1 Driven EMT in Hepatocellular Carcinoma via a SNAI1-Dependent Mechanism

The role of the epithelial-to-mesenchymal transition (EMT) during hepatocellular carcinoma (HCC) progression is well established, however the regulatory mechanisms modulating this phenomenon remain unclear. Here, we demonstrate that transcription factor glioma-associated oncogene 1 (GLI1) modulates EMT through direct up-regulation of SNAI1 and serves as a downstream effector of the transforming growth factor-b1 (TGFb1) pathway, a well-known regulator of EMT in cancer cells. Overexpression of GLI1 increased proliferation, viability, migration, invasion, and colony formation by HCC cells. Conversely, GLI1 knockdown led to a decrease in all the above-mentioned cancer-associated phenotypes in HCC cells. Further analysis of GLI1 regulated cellular functions showed that this transcription factor is able to induce EMT and identified SNAI1 as a transcriptional target of GLI1 mediating this cellular effect in HCC cells. Moreover, we demonstrated that an intact GLI1-SNAI1 axis is required by TGFb1 to induce EMT in these cells. Together, these findings define a novel cellular mechanism regulated by GLI1, which controls the growth and EMT phenotype in HCC.National Institutes of Health Grants CA100882 and CA128633 (to LRR) and CA165076; the Mayo Clinic Center for Cell Signaling in Gastroenterology (NIDDK P30DK084567) (to MEFZ); the Mayo Clinic Cancer Center (CA15083), the Mayo Clinic Center for Translational Science Activities (NIH/NCRR CTSA Grant Number KL2 RR024151), and an American Gastroenterological Association Foundation for Digestive Health and Nutrition Bridging Grant (to LRR)

TGF-β Inducible Early Gene 1 Regulates Osteoclast Differentiation and Survival by Mediating the NFATc1, AKT, and MEK/ERK Signaling Pathways

TGF-β Inducible Early Gene-1 (TIEG1) is a Krüppel-like transcription factor (KLF10) that was originally cloned from human osteoblasts as an early response gene to TGF-β treatment. As reported previously, TIEG1−/− mice have decreased cortical bone thickness and vertebral bone volume and have increased spacing between the trabeculae in the femoral head relative to wildtype controls. Here, we have investigated the role of TIEG1 in osteoclasts to further determine their potential role in mediating this phenotype. We have found that TIEG1−/− osteoclast precursors differentiated more slowly compared to wildtype precursors in vitro and high RANKL doses are able to overcome this defect. We also discovered that TIEG1−/− precursors exhibit defective RANKL-induced phosphorylation and accumulation of NFATc1 and the NFATc1 target gene DC-STAMP. Higher RANKL concentrations reversed defective NFATc1 signaling and restored differentiation. After differentiation, wildtype osteoclasts underwent apoptosis more quickly than TIEG1−/− osteoclasts. We observed increased AKT and MEK/ERK signaling pathway activation in TIEG1−/− osteoclasts, consistent with the roles of these kinases in promoting osteoclast survival. Adenoviral delivery of TIEG1 (AdTIEG1) to TIEG1−/− cells reversed the RANKL-induced NFATc1 signaling defect in TIEG1−/− precursors and eliminated the differentiation and apoptosis defects. Suppression of TIEG1 with siRNA in wildtype cells reduced differentiation and NFATc1 activation. Together, these data provide evidence that TIEG1 controls osteoclast differentiation by reducing NFATc1 pathway activation and reduces osteoclast survival by suppressing AKT and MEK/ERK signaling

A Short Distance Correctly: 13 Ways of (Not) Writing (Contrarian) Librarianship

“It’s one of those things a person has to do; sometimes a person has to go a very long distance out of his way in order to come back a short distance correctly.” –Edward Albee, The Zoo Story I It’s all fun and games until somebody gets locked in her office. By “somebody” I mean [...

An investigation of the process of change in psychopathology and exercise during inpatient treatment for adults with longstanding eating disorders

Background: Excessive exercise is recognized as a predictor of poor outcome in eating disorders. However, little is known about how excessive exercise might affect the treatment process. The aim of this study was to describe process of weekly changes in eating disorder psychopathology, general psychopathology and exercise, and the possible interactive effects of excessive exercise on these changes during inpatient treatment of longstanding eating disorders. Methods: Eighty-four patients meeting the DSM-IV criteria for Anorexia Nervosa, Bulimia Nervosa, or Eating Disorders Not Otherwise Specified received inpatient cognitive-behavioural therapy including, physical activity and nutritional counselling treatment over 12 weeks. Excessive exercise was defined as having ≥6 episodes of driven exercise during week 1 of treatment. Excessive exercisers received one additional session of individual counseling with the clinical exercise physiologist. The study used repeated measurements during treatment and collected measures of eating disorders: psychopathology (EDE-Q), general psychopathology (SCL-5), and frequencies of exercise and body mass index (BMI). Statistical analysis was performed using repeated measures ANOVA. Results: Both eating disorders and general psychopathology were reduced from admission to discharge in excessive exercisers and non-exercisers. There was an overall interaction effect between time (week) and excessive exercise for the process of exercise and eating disorders psychopathology reduction. This interaction effect was also found in week 10 vs 11 regarding general psychopathology. The excessive exercisers showed steep reduction at first, followed by a smaller increase towards the end of treatment in both eating disorder and general psychopathology; this pattern was not found among the non-exercisers. Conclusion: The process of change in exercise and psychopathology during inpatient treatment of longstanding eating disorders differs across excessive and non-excessive exercisers. Although excessive exercisers were given special attention for their exercise cognition and behavior during treatment, it is apparent that this part of treatment must be further developed

An investigation of the process of change in psychopathology and exercise during inpatient treatment for adults with longstanding eating disorders

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background: Excessive exercise is recognized as a predictor of poor outcome in eating disorders. However, little is known about how excessive exercise might affect the treatment process. The aim of this study was to describe process of weekly changes in eating disorder psychopathology, general psychopathology and exercise, and the possible interactive effects of excessive exercise on these changes during inpatient treatment of longstanding eating disorders. Methods: Eighty-four patients meeting the DSM-IV criteria for Anorexia Nervosa, Bulimia Nervosa, or Eating Disorders Not Otherwise Specified received inpatient cognitive-behavioural therapy including, physical activity and nutritional counselling treatment over 12 weeks. Excessive exercise was defined as having ≥6 episodes of driven exercise during week 1 of treatment. Excessive exercisers received one additional session of individual counseling with the clinical exercise physiologist. The study used repeated measurements during treatment and collected measures of eating disorders: psychopathology (EDE-Q), general psychopathology (SCL-5), and frequencies of exercise and body mass index (BMI). Statistical analysis was performed using repeated measures ANOVA. Results: Both eating disorders and general psychopathology were reduced from admission to discharge in excessive exercisers and non-exercisers. There was an overall interaction effect between time (week) and excessive exercise for the process of exercise and eating disorders psychopathology reduction. This interaction effect was also found in week 10 vs 11 regarding general psychopathology. The excessive exercisers showed steep reduction at first, followed by a smaller increase towards the end of treatment in both eating disorder and general psychopathology; this pattern was not found among the non-exercisers. Conclusion: The process of change in exercise and psychopathology during inpatient treatment of longstanding eating disorders differs across excessive and non-excessive exercisers. Although excessive exercisers were given special attention for their exercise cognition and behavior during treatment, it is apparent that this part of treatment must be further developed.An investigation of the process of change in psychopathology and exercise during inpatient treatment for adults with longstanding eating disorderspublishedVersio

Exercise obsession and compulsion in adults with longstanding eating disorders: Validation of the Norwegian version of the compulsive exercise test

Objectives: The objectives of this study were to (1) validate the Norwegian version of the Compulsive Exercise Test (CET) in adults with longstanding eating disorders, and (2) explore predictors of high CET-score. Methods: Adult inpatients (n = 166) with longstanding DSM-IV Anorexia Nervosa, Bulimia Nervosa (BN) or Eating Disorder not Otherwise Specified (EDNOS) completed the CET instrument, Eating Disorder examination questionnaire (EDE-Q), Beck Depression Inventory-II (BDI-II) and Symptom checklist-90 (SCL-90). A total CET score of 15 or above was defined as high CET-score. ANOVA, Confirmatory factor analysis, Pearson’s correlation, and logistic regression were used to analyze the data. Results: Cronbach’s alpha varied from 0.68 to 0.96 for the CET and its subscales. The confirmatory factor analysis showed adequate fit. Convergent validity of the CET demonstrated correlation between EDE-Q global and subscale scores and CET total score. The same pattern was found for correlation between CET subscales and EDE-Q subscales. EDE-Q global score and frequency of exercise episodes predicted high CET-score, yet 21% of the patients with high CET score had less than one episode of exercise per week. Conclusion: The Norwegian version of CET is valid and useful for assessing compulsive exercise in a sample with longstanding ED. The understanding of compulsive exercise must to a greater extent differ between obsessions and compulsions, as a significant number of patients with high CET score showed no or little exercise behavior

Effect of yoga in the treatment of eating disorders: A single-blinded randomized controlled trial with 6-months follow-up.

Aim of the Study: The aim of this study is to examine the effect of yoga treatment of eating disorders (EDs). Methods: Adult females meeting the Diagnostic and Statistical Manual-IV criteria for bulimia nervosa or ED not otherwise specified (n = 30) were randomized to 11-week yoga intervention group (2 × 90 min/week) or a control group. Outcome measures, the Eating Disorder Examination (EDE)-Interview and Eating Disorders Inventory-2 (EDI-2) scores, were administered at baseline, posttest, and at 6-month follow-up. There was a dropout rate of 30% (posttest) and 37% (6-month follow-up). Results: The intervention group showed reductions in EDE global score (P < 0.01), the EDE subscale restraint (P < 0.05), and eating concern (P < 0.01) compared to the control group. The differences between the groups increased at 6-month follow-up. There were no differences between the groups in the EDI-2 score. Conclusion: The results indicate that yoga could be effective in the treatment of ED

Effect of yoga in the treatment of eating disorders: A single-blinded randomized controlled trial with 6-months follow-up.

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Aim of the Study: The aim of this study is to examine the effect of yoga treatment of eating disorders (EDs). Methods: Adult females meeting the Diagnostic and Statistical Manual-IV criteria for bulimia nervosa or ED not otherwise specified (n = 30) were randomized to 11-week yoga intervention group (2 × 90 min/week) or a control group. Outcome measures, the Eating Disorder Examination (EDE)-Interview and Eating Disorders Inventory-2 (EDI-2) scores, were administered at baseline, posttest, and at 6-month follow-up. There was a dropout rate of 30% (posttest) and 37% (6-month follow-up). Results: The intervention group showed reductions in EDE global score (P < 0.01), the EDE subscale restraint (P < 0.05), and eating concern (P < 0.01) compared to the control group. The differences between the groups increased at 6-month follow-up. There were no differences between the groups in the EDI-2 score. Conclusion: The results indicate that yoga could be effective in the treatment of ED.publishedVersio

The modum-ED trial protocol: Comparing compassion-focused therapy and cognitive-behavioral therapy in treatment of eating disorders with and without childhood trauma: Protocol of a randomized trial

Background: The combination of eating disorder (ED) and the experience of childhood trauma leads to significant impairment and suffering. To improve treatment, it is critically important to study treatment effects, and the mechanism of these effects. The overall aim of the current project is to; (1) build knowledge on how to best treat patients with ED with and without childhood trauma, (2) develop our understanding about how change happens for these patients. We will do this by comparing two treatment models in an inpatient setting; Compassion-Focused Therapy (CFT) and cognitive-behavioral therapy (CBT) for ED. This paper describes the development, design and implementation of the trial. Methods and Design: Patients included in this randomized controlled trial will satisfy DSM-5 criteria for ED and approximately half of the patients will in addition have a history of childhood trauma. A total of 144 patients who have received either CFT or CBT are followed up 1 year after completion of the treatment. The study will collect a rich dataset of outcome measures at four time points, and process and sub-outcome measures at 13 time points. All patients will be assessed with the same clinical instruments based on current state-of-the-art methods. The primary outcome will be change in the severity of ED features as measured by the global ED examination score, and having a global ED examination score less than one standard deviation above the community mean, while secondary outcomes will relate to treatment effects on trauma symptoms, general symptoms, and quality of life. Discussion: This trial will make an important contribution to the need for evidence of effective treatment for patients with ED with or without childhood trauma. Ethics and Dissemination: The project is approved by the South-Eastern Regional Committee for Medical and Health Research Ethics of Norway (REC;2014/836)