Abrogated Inflammatory Response Promotes Neurogenesis in a Murine Model of Japanese Encephalitis

Japanese encephalitis virus (JEV) induces neuroinflammation with typical features of viral encephalitis, including inflammatory cell infiltration, activation of microglia, and neuronal degeneration. The detrimental effects of inflammation on neurogenesis have been reported in various models of acute and chronic inflammation. We investigated whether JEV-induced inflammation has similar adverse effects on neurogenesis and whether those effects can be reversed using an anti-inflammatory compound minocycline.Here, using in vitro studies and mouse models, we observed that an acute inflammatory milieu is created in the subventricular neurogenic niche following Japanese encephalitis (JE) and a resultant impairment in neurogenesis occurs, which can be reversed with minocycline treatment. Immunohistological studies showed that proliferating cells were replenished and the population of migrating neuroblasts was restored in the niche following minocycline treatment. In vitro, we checked for the efficacy of minocycline as an anti-inflammatory compound and cytokine bead array showed that production of cyto/chemokines decreased in JEV-activated BV2 cells. Furthermore, mouse neurospheres grown in the conditioned media from JEV-activated microglia exhibit arrest in both proliferation and differentiation of the spheres compared to conditioned media from control microglia. These effects were completely reversed when conditioned media from JEV-activated and minocycline treated microglia was used.This study provides conclusive evidence that JEV-activated microglia and the resultant inflammatory molecules are anti-proliferative and anti-neurogenic for NSPCs growth and development, and therefore contribute to the viral neuropathogenesis. The role of minocycline in restoring neurogenesis may implicate enhanced neuronal repair and attenuation of the neuropsychiatric sequelae in JE survivors

Experimental concepts for toxicity prevention and tissue restoration after central nervous system irradiation

Several experimental strategies of radiation-induced central nervous system toxicity prevention have recently resulted in encouraging data. The present review summarizes the background for this research and the treatment results. It extends to the perspectives of tissue regeneration strategies, based for example on stem and progenitor cells. Preliminary data suggest a scenario with individually tailored strategies where patients with certain types of comorbidity, resulting in impaired regeneration reserve capacity, might be considered for toxicity prevention, while others might be "salvaged" by delayed interventions that circumvent the problem of normal tissue specificity. Given the complexity of radiation-induced changes, single target interventions might not suffice. Future interventions might vary with patient age, elapsed time from radiotherapy and toxicity type. Potential components include several drugs that interact with neurodegeneration, cell transplantation (into the CNS itself, the blood stream, or both) and creation of reparative signals and a permissive microenvironment, e.g., for cell homing. Without manipulation of the stem cell niche either by cell transfection or addition of appropriate chemokines and growth factors and by providing normal perfusion of the affected region, durable success of such cell-based approaches is hard to imagine

The problematic use of Information and Communication Technologies (ICT) in adolescents by the cross sectional JOITIC study

Background: The emerging field of Information and Communications Technology (ICT) has brought about new interaction styles. Its excessive use may lead to addictive behaviours. The objective is to determine the prevalence of the problematic use of ICT such as Internet, mobile phones and video games, among adolescents enrolled in mandatory Secondary Education (ESO in Spanish) and to examine associated factors. Methods: Cross sectional, multi-centric descriptive study. Population: 5538 students enrolled in years one to four of ESO at 28 schools in the Vallès Occidental region (Barcelona, Spain). Data collection: self-administered socio-demographic and ICT access questionnaire, and validated questionnaires on experiences related to the use of the Internet, mobile phones and video games (CERI, CERM, CERV). Results: Questionnaires were collected from 5,538 adolescents between the ages of 12 and 20 (77.3 % of the total response), 48.6 % were females. Problematic use of the Internet was observed in 13.6 % of the surveyed individuals; problematic use of mobile phones in 2.4 % and problematic use in video games in 6.2 %. Problematic Internet use was associated with female students, tobacco consumption, a background of binge drinking, the use of cannabis or other drugs, poor academic performance, poor family relationships and an intensive use of the computer. Factors associated with the problematic use of mobile phones were the consumption of other drugs and an intensive use of these devices. Frequent problems with video game use have been associated with male students, the consumption of other drugs, poor academic performance, poor family relationships and an intensive use of these games. Conclusions: This study offers information on the prevalence of addictive behaviours of the Internet, mobile phones and video game use. The problematic use of these ICT devices has been related to the consumption of drugs, poor academic performance and poor family relationships. This intensive use may constitute a risk marker for ICT addictio

Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

Hedgehog signaling drives oncogenesis in several cancers and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened. However, resistance to Smoothened inhibitors occurs via genetic changes of Smoothened or other downstream Hedgehog components. Here, we overcome these resistance mechanisms by modulating GLI transcription via inhibition of BET bromodomain proteins. We show the BET bromodomain protein, BRD4, regulates GLI transcription downstream of SMO and SUFU and chromatin immunoprecipitation studies reveal BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites upon treatment with JQ1, a small molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists