RESUMO
Mitochondrial superoxide (O2-) production is implicated in aging, neurodegenerative disease, and most recently epilepsy. Yet the specific contribution of neuronal O2- to these phenomena is unclear. Here, we selectively deleted superoxide dismutase-2 (SOD2) in neuronal basic helix-loop-helix transcription factor (NEX)-expressing cells restricting deletion to a subset of excitatory principle neurons primarily in the forebrain (cortex and hippocampus). This resulted in nSOD2 KO mice that lived into adulthood (2-3 months) with epilepsy, selective loss of neurons, metabolic rewiring and a marked mitohormetic gene response. Surprisingly, expression of an astrocytic gene, glial fibrillary acidic protein (GFAP) was significantly increased relative to WT. Further studies in rat primary neuron-glial cultures showed that increased mitochondrial O2-, specifically in neurons, was sufficient to upregulate GFAP. These results suggest that neuron-specific mitochondrial O2- is sufficient to drive a complex and catastrophic epileptic phenotype and highlights the ability of SOD2 to act in a cell-nonautonomous manner to influence an astrocytic response.
Assuntos
Astrócitos/patologia , Epilepsia/patologia , Transtornos do Metabolismo de Glucose/patologia , Mitocôndrias , Neurônios , Estresse Oxidativo , Animais , Comportamento Animal , Eletroencefalografia , Epilepsia/psicologia , Proteína Glial Fibrilar Ácida/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Cultura Primária de Células , Ratos , Superóxido Dismutase/genética , Superóxidos/metabolismoRESUMO
PURPOSE: Previous studies have examined the association between ABO blood group and ovarian cancer risk, with inconclusive results. METHODS: In eight studies participating in the Ovarian Cancer Association Consortium, we determined ABO blood groups and diplotypes by genotyping 3 SNPs in the ABO locus. Odds ratios and 95 % confidence intervals were calculated in each study using logistic regression; individual study results were combined using random effects meta-analysis. RESULTS: Compared to blood group O, the A blood group was associated with a modestly increased ovarian cancer risk: (OR: 1.09; 95 % CI: 1.01-1.18; p = 0.03). In diplotype analysis, the AO, but not the AA diplotype, was associated with increased risk (AO: OR: 1.11; 95 % CI: 1.01-1.22; p = 0.03; AA: OR: 1.03; 95 % CI: 0.87-1.21; p = 0.76). Neither AB nor the B blood groups were associated with risk. Results were similar across ovarian cancer histologic subtypes. CONCLUSION: Consistent with most previous reports, the A blood type was associated modestly with increased ovarian cancer risk in this large analysis of multiple studies of ovarian cancer. Future studies investigating potential biologic mechanisms are warranted.