Exposure to ambient air pollution is a serious and common public health concern associated with growing morbidity and mortality worldwide. In the last decades, the adverse effects of air pollution on the pulmonary and cardiovascular systems have been well established in a series of major epidemiological and observational studies. In the recent past, air pollution has also been associated with diseases of the central nervous system (CNS), including stroke, Alzheimer's disease, Parkinson's disease, and neurodevelopmental disorders. It has been demonstrated that various components of air pollution, such as nanosized particles, can easily translocate to the CNS where they can activate innate immune responses. Furthermore, systemic inflammation arising from the pulmonary or cardiovascular system can affect CNS health. Despite intense studies on the health effects of ambient air pollution, the underlying molecular mechanisms of susceptibility and disease remain largely elusive. However, emerging evidence suggests that air pollution-induced neuroinflammation, oxidative stress, microglial activation, cerebrovascular dysfunction, and alterations in the blood-brain barrier contribute to CNS pathology. A better understanding of the mediators and mechanisms will enable the development of new strategies to protect individuals at risk and to reduce detrimental effects of air pollution on the nervous system and mental health.

Intranasal delivery (ID) of neuroprotective drugs is an area of great interest. Among the administration strategies used at present, ID of EPO is the most promising. Further preclinical and clinical studies are needed to evaluate the potential significance of this alternative route for increasing EPO bioavailability and decreasing side effects.

Understanding migration, population and differentiation of primordial neural crest cells will help in evolving biology of neuroblastoma. P16 is a tumour suppressor gene contributing in cell cycle arrest as cyclin dependent kinase inhibitor. Methylation is an important mechanism for silencing tumor suppressor genes. The aim of this study was to evaluate the role of p16 and its methylation pattern in neuroblastoma tumorigenesis. This study included 23 cases (11 male; 12 female) and 31 samples from archival paraffin embedded tissues. P16 was studied in 5 samples of normal adrenal medullar tissue, 5 samples of adrenal tissue including blastic rests, 5 samples of neuroblastoma in situ tissue and in 8 samples of neuroblastoma tissues primary and after chemotherapy in each group. The adrenal gland tissues were obtained from paediatric autopsy cases. Expression of p16 was searched by immunohistochemistry. Methylation specific PCR was used to detect the methylation rate of p16. The age range of autopsy cases was between 20 weeks of foetal age and 36 months of infant age. The mean age of neuroblastoma cases was 45 months. P16 expression was positive in normal adrenal tissues, in one of 5 samples of adrenal blastic rest tissue and in all of samples of after chemotherapy; while no expression was observed in neuroblastoma and neuroblastoma in situ tissues. P16 methylation was observed in samples of neuroblastoma in situ and primary neuroblastoma tissues. Our results suggest that p16 and its methylation seems to play role in neuroblastoma tumorigenesis and in the migration, population and differentiation of primordial neural crest cells. Inhibitors of DNA methylation may provide a useful tool for restoring p16 activity in neuroblastoma treatment.

Objectives: The aim of the present study is to investigate the clinical significance of epigenetic changes in neuroblastoma, we evaluated the relationship between therapeutic variables and the pattern of gene methylation in neuroblastoma cell lines. Methods: In this minimal residual disease model, cytotoxic effects of blocked p14ARF by a demethylating agent on KELLY and SHSY-5Y human neuroblastoma cell lines were assessed following addition of the drugs used in the Turkish Pediatric Oncology Group (TPOG) chemotherapy protocol. Drug induced effects on cell viability, cell damage and apoptotic cell death ratio were assessed with trypan blue dying. Cytotoxic effects differed among the used neuroblastoma cell lines. For the investigation of mechanisms of this effect, p14ARF gen methylation and expression levels, and MYCN expression levels were targeted. Expressions of mRNA and protein were determined with real-time PCR and ELISA, respectively. Results: The p14ARF gene expression levels in KELLY 5-aza-CdR, Vincristin, Vincristin+5-aza-CdR, Dacarbazine, Ifosfamide+5-aza-CdR, Doxorubicine+5-aza-CdR, Etoposide+5-aza-CdR groups were found to be significantly higher than those measured in corresponding groups of SHSY-5Y (p<0.05). The percentages of p14 ARF gene promoter unmethylation were higher in MYCN (-) groups than MYCN (+) groups (p=0.034). Conclusion:In this pioneering study we suggest not only a new therapeutic approach for early or late relapses following the standard treatment protocols, but also demonstrate the effect of chemoterapeutic agents on p14 ARF gene. The present study suggests that clinically aggressive neuroblastoma cell lines have aberrant methylation of p14ARF genes and provides a rationale for exploring treatment strategies that include demethylating agents.