ABSTRACT
We have employed a biological chemistry approach to dissect the mechanisms underpinning cellular responses to oxidant stress and to develop biologically relevant anti-oxidants. We have used telomere biology to define cellular stress responses and have observed telomere independent, p21- and p16-dependent stasis following oxidative insult in human fibroblasts. This was accompanied by a [corrected] reduction in XRCC5 expression and a reduction in [corrected] SIRT 1 expression. Using these markers in conjunction with senescence-associated beta-galactosidase expression, we have developed and screened novel nitrone based anti-oxidant compounds. We have identified functional compounds that are unsuitable for use in primary human cells. This has allowed subsequent identification of suitably structured compounds that act as superior biological anti-oxidants, which have potential for use in clinical interventions.
Subject(s)
Antioxidants/pharmacology , Drug Design , Nitrogen Oxides/chemistry , Telomere/drug effects , Antioxidants/chemistry , Bromodeoxyuridine/metabolism , Cells, Cultured , Cellular Senescence , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p21/genetics , DNA Helicases/genetics , Dose-Response Relationship, Drug , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Gene Expression/drug effects , Humans , Hydrogen Peroxide/pharmacology , Infant, Newborn , Ku Autoantigen , Molecular Structure , Oxidants/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , Structure-Activity Relationship , Telomere/genetics , Telomere/metabolism , beta-Galactosidase/metabolismABSTRACT
The APOE gene is located on chromosome 19, and the three common alleles are designated epsilon2, epsilon3, and epsilon4. The epsilon4 allele is associated with increased plasma cholesterol, atherosclerosis and cardiovascular disease, Alzheimer's disease, and decreased longevity. The objective of the present study was to estimate the distribution of APOE alleles in the Greek population by DNA analysis. The material consisted of 216 voluntary, healthy Greek blood donors (146 males/70 females). The APOE allele frequencies were epsilon2: 5.3%, epsilon3: 88.2%, epsilon4: 6.5%. The epsilon4 allele frequency of 6.5% in the Greek population is, together with the frequency in the Chinese population, among the lowest in the world.
