| 1. |
- Chavali, Pavithra Lakshminarasimhan, et al.
(author)
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TLX activates MMP-2, promotes self-renewal of tumor spheres in neuroblastoma and correlates with poor patient survival.
- 2014
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In: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 449:5
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Journal article (peer-reviewed)abstract
- Nuclear orphan receptor TLX (Drosophila tailless homolog) is essential for the maintenance of neural stem/progenitor cell self-renewal, but its role in neuroblastoma (NB) is not well understood. Here, we show that TLX is essential for the formation of tumor spheres in three different NB cell lines, when grown in neural stem cell media. We demonstrate that the knock down of TLX in IMR-32 cells diminishes its tumor sphere-forming capacity. In tumor spheres, TLX is coexpressed with the neural progenitor markers Nestin, CD133 and Oct-4. In addition, TLX is coexpressed with the migratory neural progenitor markers CD15 and matrix metalloproteinase-2 (MMP-2) in xenografts of primary NB cells from patients. Subsequently, we show the effect of TLX on the proliferative, invasive and migratory properties of IMR-32 cells. We attribute this to the recruitment of TLX to both MMP-2 and Oct-4 gene promoters, which resulted in the respective gene activation. In support of our findings, we found that TLX expression was high in NB patient tissues when compared with normal peripheral nervous system tissues. Further, the Kaplan-Meier estimator indicated a negative correlation between TLX expression and survival in 88 NB patients. Therefore, our results point at TLX being a crucial player in progression of NB, by promoting self-renewal of NB tumor-initiating cells and altering their migratory and invasive properties.
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| 2. |
- Johansson, Erik, et al.
(author)
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Nuclear receptor TLX inhibits TGF-beta signaling in glioblastoma
- 2016
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In: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 343:2, s. 118-125
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Journal article (peer-reviewed)abstract
- TLX (also called NR2E1) is an orphan nuclear receptor that maintains sternness of neuronal stem cells. TLX is highly expressed in the most malignant form of glioma, glioblastoma multiforme (GBM), and is important for the proliferation and maintenance of the stem/progenitor cells of the tumor. Transforming Growth Factor-beta (TGF-beta) is a cytokine regulating many different cellular processes such as differentiation, migration, adhesion, cell death and proliferation. TGF-beta has an important function in cancer where it can work as either a tumor suppressor or oncogene, depending on the cancer type and stage of tumor development. Since glioblastoma often have dysfunctional TGF-beta signaling we wanted to find out if there is any interaction between TLX and TGF-beta in glioblastoma cells. We demonstrate that knockdown of TLX enhances the canonical TGF-beta signaling response in glioblastoma cell lines. TLX physically interacts with and stabilizes Smurf1, which can ubiquitinate and target TGF-beta receptor II for degradation, whereas knockdown of TLX leads to stabilization of TGF-beta receptor II, increased nuclear translocation of Smad2/3 and enhanced expression of TGF-beta target genes. The interaction between TLX and TGF-beta may play an important role in the regulation of proliferation and tumor-initiating properties of glioblastoma cells.
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| 3. |
- Sobhan, Praveen, et al.
(author)
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ASK1 regulates the survival of neuroblastoma cells by interacting with TLX and stabilizing HIF-1α
- 2017
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In: Cellular Signalling. - : Elsevier BV. - 0898-6568. ; 30, s. 104-117
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Journal article (peer-reviewed)abstract
- Elevated expression of TLX (also called as NR2E1) in neuroblastoma (NB) correlateswith unfavorable prognosis, and TLX is required for self-renewal of NB cells. Knockdown of TLX has been shown to reduce the NB sphereforming ability. ASK1 (MAP3K5) and TLX expression are both enhanced in SP (side population) NB and patient-derived primary NB sphere cell lines, but the majority of non-SP NB lines express lower ASK1 expression. We found that ASK1 phosphorylated and stabilized TLX, which led induction of HIF-1α, and its downstream VEGF-A in an Akt dependent manner. In depleting ASK1 upon hypoxia, TLX decreased and the apoptosis ratio of NB cells was enhanced, while low-ASK1-expressing NB cell lines were refractory in TUNEL assay by using flow cytometry. Interestingly, primary NB spheres cell lines express only high levels of active pASK1Thr-838 but the established cell lines expressed inhibitory pASK1Ser-966, and both could be targeted by ASK1 depletion. We report a novel pro-survival role of ASK1 in the tumorigenic NB cell populations, which may be applied as a therapeutic target, inducing apoptosis specifically in cancer stem cells.
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| 4. |
- Vizlin-Hodzic, Dzeneta, et al.
(author)
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Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages
- 2017
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7:1
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Journal article (peer-reviewed)abstract
- Neuro-inflammation and neuronal communication are considered as mis-regulated processes in the aetiology and pathology of bipolar disorder (BD). Which and when specific signal pathways become abnormal during the ontogeny of bipolar disorder patients is unknown. To address this question, we applied induced pluripotent stem cell (iPSC) technology followed by cortical neural differentiation on adipocyte-derived cells from BD type I patients (with psychotic episodes in psychiatric history) and healthy volunteers (controls). RNA sequencing in iPSC and cortical neural stem cell (NSC) lines were used to examine alterations between the transcriptomes from BD I and control samples during transition from the pluripotent stage towards the neural developmental stage. At the iPSC stage, the most highly significant differentially expressed gene (DEG) was the NLRP2 inflammasome (P = 2.66 × 10-10). Also among 42 DEGs at the NSC stage, NLRP2 showed the strongest statistical significance (P = 3.07 × 10-19). In addition, we have also identified several cytoskeleton-associated genes as DEGs from the NSC stage, such as TMP2, TAGLN, and ACTA2; the former two genes are recognised for the first time to be associated with BD. Our results also suggest that iPSC-derived BD-cortical NSCs carry several abnormalities in dopamine and GABA receptor canonical pathways, underlining that our in vitro BD model reflects pathology in the CNS. This would indicate that mis-regulated gene expression of inflammatory, neurotransmitter, and cytoskeletal signalling occurs during early foetal brain development of BD I patients.
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| 5. |
- Zhai, Qiwei, 1987-, et al.
(author)
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Physical training for patients with depression and anxiety - a randomized controlled study
- 2021
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In: European psychiatry. - : Cambridge University Press. - 0924-9338 .- 1778-3585. ; 64:Suppl. 1, s. S690-S690
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Journal article (other academic/artistic)abstract
- Introduction: Pharmaceutical treatment and psychotherapy constitute the most common treatment methods for depression and anxiety. Physical training has been shown to have comparable effect to cognitive behavioral therapy in treatment of mild to moderate depression and anxiety. Physically active individuals also show lower risks to develop depression and relapse in depression.Objectives: The objectives are to evaluate how physical activity can affect depressive and anxiety symptoms, by examining biomarkers in the blood and from the gut and also by measuring cognitive functions. Hopefully, this can lead to new treatment strategies for patients with depression and anxiety.Methods: 102 patients are randomized to two groups and undergo 12 weeks intervention as add-on to standard outpatient psychiatric treatment. The first group will participate in physical training three times per week and the other group will receive relaxation therapy on a weekly basis. Daily activity intensity will be measured before and at the last week of intervention with an accelerometer. Blood and faeces sample collection, symptom grading by clinician together with self-rating scales and cognitive screening will be performed at baseline, week 12 and one year of follow-up. The cognitive screenings are performed digitally in cooperation with Mindmore.Results: The RCT is currently recruiting patients at the Department of Psychiatry of Örebro University Hospital.Conclusions: The project aims to be holistic in its approach, combining the defining clinical psychiatric symptoms in patients who have both depression and anxiety with the finding and evaluation of new biomarkers from blood and gut to improve cognitive functions.
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