RESUMO
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.
Assuntos
Antioxidantes/farmacologia , Desenho de Fármacos , Óxidos de Nitrogênio/química , Telômero/efeitos dos fármacos , Antioxidantes/química , Bromodesoxiuridina/metabolismo , Células Cultivadas , Senescência Celular , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , DNA Helicases/genética , Relação Dose-Resposta a Droga , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Recém-Nascido , Autoantígeno Ku , Estrutura Molecular , Oxidantes/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Relação Estrutura-Atividade , Telômero/genética , Telômero/metabolismo , beta-Galactosidase/metabolismoRESUMO
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.