The use of telomere biology to identify and develop superior nitrone based anti-oxidants.
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.
Sklavounou
E
E
Division of Cancer Sciences and Molecular Pathology University of Glasgow, Glasgow G12 8QQ, UK.
Hay
A
A
Ashraf
N
N
Lamb
K
K
Brown
E
E
Mac Intyre
A
A
George
W D
WD
Hartley
R C
RC
Shiels
P G
PG
D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007231:Infant, Newborn; D000072200:Ku Autoantigen; D015394:Molecular Structure; D009589:Nitrogen Oxides / Q000737:chemistry*; D016877:Oxidants / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D016615:Telomere / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D000975:Antioxidants; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009589:Nitrogen Oxides; D016877:Oxidants; C015388:nitrones; D006861:Hydrogen Peroxide; D001616:beta-Galactosidase; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen; D001973:Bromodeoxyuridine