The search for effective treatments that prevent oxidative stress associated with premature ageing and neurodegenerative diseases is an important area of neurochemical research. As age- and disease-related oxidative stress is frequently associated with mitochondrial dysfunction, amphiphilic antioxidant agents of high stability and selectivity that target these organelles can provide on-site protection.
Forkhead box O (FOXO) transcription factors control diverse cellular functions, such as cell death, metabolism, and longevity. We analyzed FOXO3/FKHRL1 expression and subcellular localization in tumor sections of neuroblastoma patients and observed a correlation between nuclear FOXO3 and high caspase-8 expression. In neuroblastoma caspase-8 is frequently silenced by DNA methylation. Conditional FOXO3 activated caspase-8 gene expression but did not change the DNA-methylation pattern of regulatory sequences in the caspase-8 gene.
The International Journal of Neuropsychopharmacology
Unraveling the epigenetic status of neuronal cells in the brain is critical to our understanding of the pathophysiology of psychiatric disorders, which may reflect a complex interaction between genetic and environmental factors. Several epigenetic studies of mood disorders have been conducted with postmortem brains. However, proper interpretation of the results is hampered by our scant understanding of the effects of mood stabilizers on the epigenetic status of neuronal cells.
Blonanserin is a second-generation antipsychotic drug for schizophrenia. The pharmacological actions of blonanserin are shown to be the antagonism of dopamine receptor 2 and serotonin receptors. However, its molecular mechanisms in brain cells have not been fully characterized. Accumulating evidence suggests that antipsychotic drugs and mood stabilizers show epigenetic effects on a wide range of genes in animal and cellular models. We performed genome-wide DNA methylation analysis targeting 479,814 CpG sites of cultured human neuroblastoma cells administered with blonanserin.
Histone H3K4 demethylase LSD1 plays an important role in stem cell biology, especially in the maintenance of the silencing of differentiation genes. However, how the function of LSD1 is regulated and the differentiation genes are derepressed are not understood. Here, we report that elimination of LSD1 promotes embryonic stem cell (ESC) differentiation toward neural lineage. We showed that the destabilization of LSD1 occurs posttranscriptionally via the ubiquitin-proteasome pathway by an E3 ubiquitin ligase, Jade-2.
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Epigenetic regulation may be involved in the pathophysiology of mental disorders, such as schizophrenia and bipolar disorder, and in the pharmacological action of drugs. Characterizing the epigenetic effects of drugs is an important step to optimal treatment. We performed comprehensive and gene-specific DNA methylation analyses of quetiapine using human neuroblastoma cells. Human neuroblastoma cells were cultured with quetiapine for 8 days, and DNA methylation analysis was performed using Infinium HumanMethylation27 BeadChip. A total of 1173 genes showed altered DNA methylation.
We have shown that melatonin induces histone hyperacetylation in vitro and in vivo. To clarify the mechanisms involved, we have now investigated its effects on histone acetylation and signaling pathways in human SH-SY5Y neuroblastoma cells, which express melatonin MT1 receptors. Melatonin caused significant concentration-dependent increases in both histone H3 and H4 acetylation. Blockade of melatonin receptors with luzindole abolished the histone hyperacetylating effect of melatonin, whereas inhibition of MAPK-ERK by PD98059 attenuated but did not block this effect.
Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association
Cosmetic, pharmaceutical, food and confectionary industries make increasing use of plant extracts in their products. Despite the widespread use of products containing plant extracts, the mechanisms of their effects are not fully characterized. Bergamot essential oil (BEO; Citrus bergamia, Risso) is a well-known plant extract used in aromatherapy and it has analgesic, anxiolytic and neuroprotective effects in rodents. To elicit neuroprotection, BEO recruits Akt prosurvival pathways. However, Akt stimulates cell proliferation, which may also pose risks for health in case of prolonged use.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that shows cognitive deficits and memory impairment. Extract from the leaves of Gotu Kola (Centella Asiatica) have been used as an alternative medicine for memory improvement in Indian Ayurvedic system of medicine for a long time. Although several studies have revealed its effect in ameliorating the cognitive impairment in rat models of AD and stimulating property on neuronal dendrites of hippocampal region, the molecular mechanism of Gotu Kola on neuroprotection still remains to be elucidated.
Proceedings of the National Academy of Sciences of the United States of America
Taxol (Paclitaxel) is an important natural product for the treatment of solid tumors. Despite a well documented tubulin-stabilizing effect, many side effects of taxol therapy cannot be explained by cytoskeletal mechanisms. In the present study submicromolar concentrations of taxol, mimicking concentrations found in patients, induced cytosolic calcium (Ca(2+)) oscillations in a human neuronal cell line. These oscillations were independent of extracellular and mitochondrial Ca(2+) but dependent on intact signaling via the phosphoinositide signaling pathway.