8 research outputs found
PARP-3 and APLF function together to accelerate nonhomologous end joining
PARP-3 is a member of the ADP-ribosyl transferase superfamily of unknown function. We show that PARP-3 is stimulated by DNA double-strand breaks (DSBs) in vitro and functions in the same pathway as the poly (ADP-ribose)-binding protein APLF to accelerate chromosomal DNA DSB repair. We implicate PARP-3 in the accumulation of APLF at DSBs and demonstrate that APLF promotes the retention of XRCC4/DNA ligase IV complex in chromatin, suggesting that PARP-3 and APLF accelerate DNA ligation during nonhomologous end-joining (NHEJ). Consistent with this, we show that class switch recombination in Aplfβ/β B cells is biased toward microhomology-mediated end-joining, a pathway that operates in the absence of XRCC4/DNA ligase IV, and that the requirement for PARP-3 and APLF for NHEJ is circumvented by overexpression of XRCC4/DNA ligase IV. These data identify molecular roles for PARP-3 and APLF in chromosomal DNA double-strand break repair reactions
Why nutraceuticals do not prevent or treat Alzheimer's disease
<p>Abstract</p> <p>A great deal of research has pointed to deleterious roles of metal ions in the development of Alzheimer's disease. These include: i) the precipitation and aggregation of amyloid Ξ² (AΞ²) peptides to form senile plaques and neurofibrillary tangles, and/or ii) the augmentation of oxidative stress by metal ion mediated production and activation of hydrogen peroxide. The growing trend in nutraceutical intake is in part a result of the belief that they postpone the development of dementias such as Alzheimer's disease. However, pathogenic events centred on metal ions are expected to be aggravated by frequent nutraceutical intake. Novel therapeutic approaches centred on chelators with specificity for copper and iron ions should be fully explored.</p
ΠΠΎΠ±Π°Π²ΠΊΠΈ Π·Π°Π»ΡΠ·Π°: ΡΠ²ΠΈΠ΄ΠΊΠ΅ Π·Π°ΡΠ²ΠΎΡΠ½Π½Ρ ΡΠ° Π²ΡΠ΄Π΄Π°Π»Π΅Π½Ρ Π½Π°ΡΠ»ΡΠ΄ΠΊΠΈ
Co-supplementation of ferrous salts with vitamin C exacerbates oxidative stress in the gastrointestinal tract leading to ulceration in healthy individuals, exacerbation of chronic gastrointestinalΒ inflammatory diseases and can lead to cancer. Reactive oxygen and nitrogen species (RONS) have been ascribed an important role in oxidative stress. Redox-active metal ions such as Fe (II)Β and Cu (I) further activate RONS and thus perpetuate their damaging effects. Ascorbic acid can exert a pro-oxidant effect by its interaction with metal ions via a number of established RONSΒ generating systems which are reviewed here. Further studies are required to examine the detrimental effects of nutraceuticals especially in chronic inflammatory conditions which co-presentΒ with anaemiaΠΠΎΠΌΠ±ΠΈΠ½ΠΈΡΠΎΠ²Π°Π½Π½ΡΠ΅ Π΄ΠΎΠ±Π°Π²ΠΊΠΈ, ΡΠΎΠ΄Π΅ΡΠΆΠ°ΡΠΈΠ΅ ΡΠΎΠ»ΠΈ ΠΆΠ΅Π»Π΅Π·Π° ΠΈ Π²ΠΈΡΠ°ΠΌΠΈΠ½ Π‘, ΡΡΠΈΠ»ΠΈΠ²Π°ΡΡ ΠΎΠΊΡΠΈΠ΄Π°ΡΠΈΠ²Π½ΡΠΉ ΡΡΡΠ΅ΡΡ Π² ΠΆΠ΅Π»ΡΠ΄ΠΎΡΠ½ΠΎ-ΠΊΠΈΡΠ΅ΡΠ½ΠΎΠΌ ΡΡΠ°ΠΊΡΠ΅, ΡΡΠΎ ΠΏΡΠΈΠ²ΠΎΠ΄ΠΈΡ ΠΊ ΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π½ΠΈΡ ΡΠ·Π²Ρ Ρ Π·Π΄ΠΎΡΠΎΠ²ΡΡ
Β Π»ΠΈΡ, ΠΎΠ±ΠΎΡΡΡΠ΅Π½ΠΈΡ Ρ
ΡΠΎΠ½ΠΈΡΠ΅ΡΠΊΠΈΡ
ΠΆΠ΅Π»ΡΠ΄ΠΎΡΠ½ΠΎ-ΠΊΠΈΡΠ΅ΡΠ½ΡΡ
Π²ΠΎΡΠΏΠ°Π»ΠΈΡΠ΅Π»ΡΠ½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ ΠΈ ΠΌΠΎΠΆΠ΅Ρ Π²ΡΠ·Π²Π°ΡΡ ΡΠ°ΠΊ. ΠΠΏΠΈΡΠ°Π½ΠΎ, ΡΡΠΎ Π°ΠΊΡΠΈΠ²Π½ΡΠ΅ ΡΠΎΡΠΌΡ ΠΊΠΈΡΠ»ΠΎΡΠΎΠ΄Π° ΠΈ Π°Π·ΠΎΡΠ° (reactive oxygen andΒ nitrogen species, RONS) ΠΈΠ³ΡΠ°ΡΡ Π²Π°ΠΆΠ½ΡΡ ΡΠΎΠ»Ρ Π² ΠΎΠΊΠΈΡΠ»ΠΈΡΠ΅Π»ΡΠ½ΠΎΠΌ ΡΡΡΠ΅ΡΡΠ΅. ΠΠΎΠ½Ρ ΡΠ΅Π΄ΠΎΠΊΡ-Π°ΠΊΡΠΈΠ²Π½ΡΡ
ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠ², ΡΠ°ΠΊΠΈΡ
ΠΊΠ°ΠΊ ΠΆΠ΅Π»Π΅Π·ΠΎ (Fe (II)), ΠΌΠ΅Π΄Ρ ΠΈ (Cu (I)), Π΄ΠΎΠΏΠΎΠ»Π½ΠΈΡΠ΅Π»ΡΠ½ΠΎ Π°ΠΊΡΠΈΠ²ΠΈΡΡΡΡ RONSΒ ΠΈ, ΡΠ°ΠΊΠΈΠΌ ΠΎΠ±ΡΠ°Π·ΠΎΠΌ, ΠΏΠΎΠ΄Π΄Π΅ΡΠΆΠΈΠ²Π°ΡΡ ΠΈΡ
ΠΏΠΎΠ²ΡΠ΅ΠΆΠ΄Π°ΡΡΠ΅Π΅ Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅. ΠΡΠΊΠΎΡΠ±ΠΈΠ½ΠΎΠ²Π°Ρ ΠΊΠΈΡΠ»ΠΎΡΠ° ΠΌΠΎΠΆΠ΅Ρ ΠΎΠΊΠ°Π·ΡΠ²Π°ΡΡ ΠΏΡΠΎΠΎΠΊΠΈΡΠ»ΠΈΡΠ΅Π»ΡΠ½ΡΠΉ ΡΡΡΠ΅ΠΊΡ ΡΠ΅ΡΠ΅Π· Π΅Π΅ Π²Π·Π°ΠΈΠΌΠΎΠ΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ Ρ ΠΈΠΎΠ½Π°ΠΌΠΈ ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠ² Β Ρ ΠΏΠΎΠΌΠΎΡΡΡ ΡΡΠ΄Π° ΡΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½Π½ΡΡ
ΡΠΈΡΡΠ΅ΠΌ, Π³Π΅Π½Π΅ΡΠΈΡΡΡΡΠΈΡ
RONS, ΠΊΠΎΡΠΎΡΡΠ΅ ΡΠ°ΡΡΠΌΠΎΡΡΠ΅Π½Ρ Π² Π΄Π°Π½Π½ΠΎΠΉ ΡΡΠ°ΡΡΠ΅. ΠΠ΅ΠΎΠ±Ρ
ΠΎΠ΄ΠΈΠΌΡ Π΄Π°Π»ΡΠ½Π΅ΠΉΡΠΈΠ΅ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ Ρ ΡΠ΅Π»ΡΡ ΠΈΠ·ΡΡΠ΅Π½ΠΈΡ Π½Π΅Π³Π°ΡΠΈΠ²Π½ΡΡ
Β ΠΏΠΎΡΠ»Π΅Π΄ΡΡΠ²ΠΈΠΉ Π²Π»ΠΈΡΠ½ΠΈΡ Π½ΡΡΡΠΈΡΠ΅Π²ΡΠΈΠΊΠΎΠ², ΠΎΡΠΎΠ±Π΅Π½Π½ΠΎ ΠΏΡΠΈ Ρ
ΡΠΎΠ½ΠΈΡΠ΅ΡΠΊΠΈΡ
Π²ΠΎΡΠΏΠ°Π»ΠΈΡΠ΅Π»ΡΠ½ΡΡ
ΡΠΎΡΡΠΎΡΠ½ΠΈΡΡ
, ΠΊΠΎΡΠΎΡΡΠ΅ ΠΏΡΠΎΡΠ΅ΠΊΠ°ΡΡ ΡΠΎΠ²ΠΌΠ΅ΡΡΠ½ΠΎ Ρ Π°Π½Π΅ΠΌΠΈΠ΅ΠΉΠΠΎΠΌΠ±ΡΠ½ΠΎΠ²Π°Π½Ρ Π΄ΠΎΠ±Π°Π²ΠΊΠΈ, ΡΠΎ ΠΌΡΡΡΡΡΡ ΡΠΎΠ»Ρ Π·Π°Π»ΡΠ·Π° Ρ Π²ΡΡΠ°ΠΌΡΠ½ Π‘, ΠΏΠΎΡΠΈΠ»ΡΡΡΡ ΠΎΠΊΡΠΈΠ΄Π°ΡΠΈΠ²Π½ΠΈΠΉ ΡΡΡΠ΅Ρ Ρ ΡΠ»ΡΠ½ΠΊΠΎΠ²ΠΎ-ΠΊΠΈΡΠΊΠΎΠ²ΠΎΠΌΡ ΡΡΠ°ΠΊΡΡ, ΡΠΎ ΠΏΡΠΈΠ·Π²ΠΎΠ΄ΠΈΡΡ Π΄ΠΎ ΡΠΎΠ·Π²ΠΈΡΠΊΡ Π²ΠΈΡΠ°Π·ΠΊΠΈ Ρ Π·Π΄ΠΎΡΠΎΠ²ΠΈΡ
ΠΎΡΡΠ±, Π΄ΠΎΒ Π·Π°Π³ΠΎΡΡΡΠ΅Π½Π½Ρ Ρ
ΡΠΎΠ½ΡΡΠ½ΠΈΡ
ΡΠ»ΡΠ½ΠΊΠΎΠ²ΠΎ-ΠΊΠΈΡΠΊΠΎΠ²ΠΈΡ
Π·Π°ΠΏΠ°Π»ΡΠ½ΠΈΡ
Π·Π°Ρ
Π²ΠΎΡΡΠ²Π°Π½Ρ Ρ ΠΌΠΎΠΆΠ΅ ΡΠΏΡΠΈΡΠΈΠ½ΠΈΡΠΈ ΡΠ°ΠΊ. ΠΠΏΠΈΡΠ°Π½ΠΎ, ΡΠΎ Π°ΠΊΡΠΈΠ²Π½Ρ ΡΠΎΡΠΌΠΈ ΠΊΠΈΡΠ½Ρ ΡΠ° Π°Π·ΠΎΡΡ (reactive oxygen and nitrogen species, RONS)Β Π²ΡΠ΄ΡΠ³ΡΠ°ΡΡΡ Π²Π°ΠΆΠ»ΠΈΠ²Ρ ΡΠΎΠ»Ρ Π² ΠΎΠΊΠΈΡΠ»ΡΠ²Π°Π»ΡΠ½ΠΎΠΌΡ ΡΡΡΠ΅ΡΡ. ΠΠΎΠ½ΠΈ ΡΠ΅Π΄ΠΎΠΊΡ-Π°ΠΊΡΠΈΠ²Π½ΠΈΡ
ΠΌΠ΅ΡΠ°Π»ΡΠ², ΡΠ°ΠΊΠΈΡ
ΡΠΊ Π·Π°Π»ΡΠ·ΠΎ (Fe (II)), ΠΌΡΠ΄Ρ Ρ (Cu (I)), Π΄ΠΎΠ΄Π°ΡΠΊΠΎΠ²ΠΎ Π°ΠΊΡΠΈΠ²ΡΡΡΡ RONS Ρ, ΡΠ°ΠΊΠΈΠΌ ΡΠΈΠ½ΠΎΠΌ, ΠΏΡΠ΄ΡΡΠΈΠΌΡΡΡΡΒ ΡΡ
ΡΡΠΊΠΎΠ΄ΠΆΡΡΡΡ Π΄ΡΡ. ΠΡΠΊΠΎΡΠ±ΡΠ½ΠΎΠ²Π° ΠΊΠΈΡΠ»ΠΎΡΠ° ΠΌΠΎΠΆΠ΅ ΡΠΈΠ½ΠΈΡΠΈ ΠΏΡΠΎΠΎΠΊΠΈΡΠ½ΠΈΠΉ Π²ΠΏΠ»ΠΈΠ² ΡΠ΅ΡΠ΅Π· ΡΡ Π²Π·Π°ΡΠΌΠΎΠ΄ΡΡ Π· ΡΠΎΠ½Π°ΠΌΠΈ ΠΌΠ΅ΡΠ°Π»ΡΠ² Π·Π° Π΄ΠΎΠΏΠΎΠΌΠΎΠ³ΠΎΡ Π½ΠΈΠ·ΠΊΠΈ Π²ΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½ΠΈΡ
ΡΠΈΡΡΠ΅ΠΌ, Π³Π΅Π½Π΅ΡΡΡΡΠΈΡ
RONS, ΡΠΊΡΒ ΡΠΎΠ·Π³Π»ΡΠ½ΡΡΡ Π² ΡΡΠΉ ΡΡΠ°ΡΡΡ. ΠΠ΅ΠΎΠ±Ρ
ΡΠ΄Π½Ρ ΠΏΠΎΠ΄Π°Π»ΡΡΡ Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½Π½Ρ Π· ΠΌΠ΅ΡΠΎΡ Π²ΠΈΠ²ΡΠ΅Π½Π½Ρ Π½Π΅Π³Π°ΡΠΈΠ²Π½ΠΈΡ
Π½Π°ΡΠ»ΡΠ΄ΠΊΡΠ² Π²ΠΏΠ»ΠΈΠ²Ρ Π±ΡΠΎΠ»ΠΎΠ³ΡΡΠ½ΠΎ Π°ΠΊΡΠΈΠ²Π½ΠΈΡ
Π΄ΠΎΠ±Π°Π²ΠΎΠΊ, ΠΎΡΠΎΠ±Π»ΠΈΠ²ΠΎ ΠΏΡΠΈ Ρ
ΡΠΎΠ½ΡΡΠ½ΠΈΡ
Π·Π°ΠΏΠ°Π»ΡΠ½ΠΈΡ
ΡΡΠ°Π½Π°Ρ
, ΡΠΊΡΒ ΠΏΡΠΎΡΡΠΊΠ°ΡΡΡ ΡΠΏΡΠ»ΡΠ½ΠΎ Π· Π°Π½Π΅ΠΌΡΡ