Identification of Novel microRNAs in Post-Transcriptional Control of Nrf2 Expression and Redox Homeostasis in Neuronal, SH-SY5Y Cells.
Identification of Novel microRNAs in Post-Transcriptional Control of Nrf2 Expression and Redox Homeostasis in Neuronal, SH-SY5Y Cells.
Filed under: Addiction Rehab
PLoS One. 2012; 7(12): e51111
Narasimhan M, Patel D, Vedpathak D, Rathinam M, Henderson G, Mahimainathan L
Nuclear factor-erythroid 2-related factor 2 (Nrf2/NFE2L2), a redox-sensitive transcription factor plays a critical role in adaptation to cellular stress and affords cellular defense by initiating transcription of antioxidative and detoxification genes. While a protein can be regulated at multiple levels, control of Nrf2 has been largely studied at post-translational regulation points by Keap1. Importantly, post-transcriptional/translational based regulation of Nrf2 is less understood and to date there are no reports on such mechanisms in neuronal systems. In this context, studies involving the role of microRNAs (miRs) which are normally considered as fine tuning regulators of protein production through translation repression and/or post-transcriptional alterations, are in place. In the current study, based on in-silico analysis followed by immunoblotting and real time analysis, we have identified and validated for the first time that human NFE2L2 could be targeted by miR153/miR27a/miR142-5p/miR144 in neuronal, SH-SY5Y cells. Co-transfection studies with individual miR mimics along with either WT 3′ UTR of human Nrf2 or mutated miRNA targeting seed sequence within Nrf2 3′ UTR, demonstrated that Nrf2 is a direct regulatory target of these miRs. In addition, ectopic expression of miR153/miR27a/miR142-5p/miR144 affected Nrf2 mRNA abundance and nucleo-cytoplasmic concentration of Nrf2 in a Keap1 independent manner resulting in inefficient transactivating ability of Nrf2. Furthermore, forced expression of miRs diminished GCLC and GSR expression resulting in alteration of Nrf2 dependent redox homeostasis. Finally, bioinformatics based miRNA-disease network analysis (MDN) along with extended computational network analysis of Nrf2 associated pathologic processes suggests that if in a particular cellular scenario where any of these miR153/miR27a/miR142-5p/miR144 either individually or as a group is altered, it could affect Nrf2 thus triggering and/or determining the fate of wide range of disease outcomes.
HubMed – addiction
Affective Disorders among Patients with Borderline Personality Disorder.
Filed under: Addiction Rehab
PLoS One. 2012; 7(12): e50930
Sjåstad HN, Gråwe RW, Egeland J
The high co-occurrence between borderline personality disorder and affective disorders has led many to believe that borderline personality disorder should be considered as part of an affective spectrum. The aim of the present study was to examine whether the prevalence of affective disorders are higher for patients with borderline personality disorder than for patients with other personality disorders.In a national cross-sectional study of patients receiving mental health treatment in Norway (N?=?36 773), we determined whether psychiatric outpatients with borderline personality disorder (N?=?1 043) had a higher prevalence of affective disorder in general, and whether they had an increased prevalence of depression, bipolar disorder or dysthymia specifically. They were compared to patients with paranoid, schizoid, dissocial, histrionic, obsessive-compulsive, avoidant, dependent, or unspecified personality disorder, as well as an aggregated group of patients with personality disorders other than the borderline type (N?=?2 636). Odds ratios were computed for the borderline personality disorder group comparing it to the mixed sample of other personality disorders. Diagnostic assessments were conducted in routine clinical practice.More subjects with borderline personality disorder suffered from unipolar than bipolar disorders. Nevertheless, borderline personality disorder had a lower rate of depression and dysthymia than several other personality disorder groups, whereas the rate of bipolar disorder tended to be higher. Odds ratios showed 34% lower risk for unipolar depression, 70% lower risk for dysthymia and 66% higher risk for bipolar disorder in patients with borderline personality disorder compared to the aggregated group of other personality disorders.The results suggest that borderline personality disorder has a stronger association with affective disorders in the bipolar spectrum than disorders in the unipolar spectrum. This association may reflect an etiological relationship or diagnostic overlapping criteria.
HubMed – addiction
Distinct mechanisms mediate naive and memory CD8 T-cell tolerance.
Filed under: Addiction Rehab
Proc Natl Acad Sci U S A. 2012 Dec 10;
Jellison ER, Turner MJ, Blair DA, Lingenheld EG, Zu L, Puddington L, Lefrançois L
Peripheral tolerance to developmentally regulated antigens is necessary to sustain tissue homeostasis. We have now devised an inducible and reversible system that allows interrogation of T-cell tolerance induction in endogenous naïve and memory CD8 T cells. Our data show that peripheral CD8 T-cell tolerance can be preserved through two distinct mechanisms, antigen addiction leading to anergy for naïve T cells and ignorance for memory T cells. Induction of antigen in dendritic cells resulted in substantial expansion and maintenance of endogenous antigen-specific CD8 T cells. The self-reactive cells initially exhibited effector activity but eventually became unresponsive. Upon antigen removal, the antigen-specific population waned, resulting in development of a self-specific memory subset that recalled to subsequent challenge. In striking contrast to naïve CD8 T cells, preexisting antigen-specific memory CD8 T cells failed to expand after antigen induction and essentially ignored the antigen despite widespread expression by dendritic cells. The inclusion of inflammatory signals partially overcame memory CD8 T-cell ignorance of self-antigen. Thus, peripheral CD8 T-cell tolerance for naïve CD8 T cells depended on the continuous presence of antigen, whereas memory CD8 T cells were prohibited from autoreactivity in the absence of inflammation.
HubMed – addiction
Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells.
Filed under: Addiction Rehab
Proc Natl Acad Sci U S A. 2012 Dec 10;
Weng MT, Lee JH, Wei SC, Li Q, Shahamatdar S, Hsu D, Schetter AJ, Swatkoski S, Mannan P, Garfield S, Gucek M, Kim MK, Annunziata CM, Creighton CJ, Emanuele MJ, Harris CC, Sheu JC, Giaccone G, Luo J
Cancers with Ras mutations represent a major therapeutic problem. Recent RNAi screens have uncovered multiple nononcogene addiction pathways that are necessary for the survival of Ras mutant cells. Here, we identify the evolutionarily conserved gene enhancer of rudimentary homolog (ERH), in which depletion causes greater toxicity in cancer cells with mutations in the small GTPase KRAS compared with KRAS WT cells. ERH interacts with the spliceosome protein SNRPD3 and is required for the mRNA splicing of the mitotic motor protein CENP-E. Loss of ERH leads to loss of CENP-E and consequently, chromosome congression defects. Gene expression profiling indicates that ERH is required for the expression of multiple cell cycle genes, and the gene expression signature resulting from ERH down-regulation inversely correlates with KRAS signatures. Clinically, tumor ERH expression is inversely associated with survival of colorectal cancer patients whose tumors harbor KRAS mutations. Together, these findings identify a role of ERH in mRNA splicing and mitosis, and they provide evidence that KRAS mutant cancer cells are dependent on ERH for their survival.
HubMed – addiction
Arizona Addiction Treatment at Cottonwood de Tucson – www.cottonwooddetucson.com A high definition video of the grounds at Cottonwood de Tucson, an addiction treatment center just outside the city limits of Tucson, Arizona. Treating patients with chemical dependency, gambling addiction, eating disorders, and a range of co-occurring disorders including post-traumatic stress disorder, mood disorders, obsessive compulsive disorder and ADD At Cottonwood de Tucson a team from a variety of disciplines works together to develop an individualized recovery plan to achieve specific and meaningful goals. Treatment modalities include therapy, both group and individual, and 12 Step Meetings. EMDR (Eye Movement Desensitization and Reprocessing), Equine Therapy, Experiential therapies such as music therapy, art therapy and Playback Theater are woven in to complete the holistic approach found at Cottonwood de Tucson. A spiritually based approach to holistic therapies designed to heal the whole individual. Professional staff comprised of both medical and clinical team members provides an ongoing medical, psychiatric, psychological, cognitive, and nutritional evalutions to insure treatment is appropriate to each individual. Cottonwood de Tucson Addiction Rehab: Cottonwood de Tucson
Related Addiction Rehab Information…