PMID- 24624338
OWN - NLM
STAT- MEDLINE
DCOM- 20150616
LR  - 20211021
IS  - 2213-2317 (Print)
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 2
DP  - 2014
TI  - Inhibition of APE1/Ref-1 redox activity rescues human retinal pigment epithelial 
      cells from oxidative stress and reduces choroidal neovascularization.
PG  - 485-94
LID - 10.1016/j.redox.2014.01.023 [doi]
AB  - The effectiveness of current treatment for age related macular degeneration (AMD) 
      by targeting one molecule is limited due to its multifactorial nature and 
      heterogeneous pathologies. Treatment strategy to target multiple signaling 
      pathways or pathological components in AMD pathogenesis is under investigation 
      for better clinical outcome. Inhibition of the redox function of apurinic 
      endonuclease 1/redox factor-1 (APE1) was found to suppress endothelial 
      angiogenesis and promote neuronal cell recovery, thereby may serve as a potential 
      treatment for AMD. In the current study, we for the first time have found that a 
      specific inhibitor of APE1 redox function by a small molecule compound E3330 
      regulates retinal pigment epithelium (RPEs) cell response to oxidative stress. 
      E3330 significantly blocked sub-lethal doses of oxidized low density lipoprotein 
      (oxLDL) induced proliferation decline and senescence advancement of RPEs. At the 
      same time, E3330 remarkably decreased the accumulation of intracellular reactive 
      oxygen species (ROS) and down-regulated the productions of monocyte 
      chemoattractant protein-1 (MCP-1) and vascular endothelial growth factor (VEGF), 
      as well as attenuated the level of nuclear factor-kappaB (NF-kappaB) p65 in RPEs. A panel 
      of stress and toxicity responsive transcription factors that were significantly 
      upregulated by oxLDL was restored by E3330, including Nrf2/Nrf1, p53, NF-kappaB, 
      HIF1, CBF/NF-Y/YY1, and MTF-1. Further, a single intravitreal injection of E3330 
      effectively reduced the progression of laser-induced choroidal neovascularization 
      (CNV) in mouse eyes. These data revealed that E3330 effectively rescued RPEs from 
      oxidative stress induced senescence and dysfunctions in multiple aspects in 
      vitro, and attenuated laser-induced damages to RPE-Bruch׳s membrane complex in 
      vivo. Together with its previously established anti-angiogenic and 
      neuroprotection benefits, E3330 is implicated for potential use for AMD 
      treatment.
FAU - Li, Y
AU  - Li Y
AD  - Department of Ophthalmology, Henry Ford Health System, 1 Ford Place 5D, Detroit, 
      MI, United States ; Department of Ophthalmology, Xijing Hospital, Fourth Military 
      Medical University, Xi׳an, Shanxi, People׳s Republic of China.
FAU - Liu, X
AU  - Liu X
AD  - Department of Ophthalmology, Henry Ford Health System, 1 Ford Place 5D, Detroit, 
      MI, United States.
FAU - Zhou, T
AU  - Zhou T
AD  - Department of Ophthalmology, Henry Ford Health System, 1 Ford Place 5D, Detroit, 
      MI, United States.
FAU - Kelley, M R
AU  - Kelley MR
AD  - Herman B Wells Center for Pediatric Research, Indiana University School of 
      Medicine, Indianapolis, IN, United States.
FAU - Edwards, P
AU  - Edwards P
AD  - Department of Ophthalmology, Henry Ford Health System, 1 Ford Place 5D, Detroit, 
      MI, United States.
FAU - Gao, H
AU  - Gao H
AD  - Department of Ophthalmology, Henry Ford Health System, 1 Ford Place 5D, Detroit, 
      MI, United States.
FAU - Qiao, X
AU  - Qiao X
AD  - Department of Ophthalmology, Henry Ford Health System, 1 Ford Place 5D, Detroit, 
      MI, United States.
LA  - eng
GR  - R01 CA121168/CA/NCI NIH HHS/United States
GR  - R01 CA167291/CA/NCI NIH HHS/United States
GR  - CA121168/CA/NCI NIH HHS/United States
GR  - CA16729/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140221
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 0 (Benzoquinones)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Propionates)
RN  - 136164-66-4 (E 3330)
RN  - EC 4.2.99.18 (APEX1 protein, human)
RN  - EC 4.2.99.18 (DNA-(Apurinic or Apyrimidinic Site) Lyase)
SB  - IM
MH  - Animals
MH  - Benzoquinones/*administration & dosage
MH  - Cellular Senescence/drug effects
MH  - Choroidal Neovascularization/*drug therapy/metabolism/pathology
MH  - DNA-(Apurinic or Apyrimidinic Site) Lyase/*antagonists & inhibitors/metabolism
MH  - Disease Models, Animal
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Intravitreal Injections
MH  - Mice
MH  - Neuroprotective Agents/*administration & dosage
MH  - Oxidative Stress/*drug effects
MH  - Propionates/*administration & dosage
MH  - Retinal Pigment Epithelium/drug effects/*metabolism/pathology
PMC - PMC3949093
OTO - NOTNLM
OT  - AMD, age related macular degeneration
OT  - AP-1, activator protein 1
OT  - APE1, apurinic endonuclease 1/redox factor-1
OT  - APE1/Ref-1redox function
OT  - Age-related macular degeneration.
OT  - AhR, aryl hydrocarbon receptor
OT  - ApoE, apolipoprotein E
OT  - CBF/NF-Y/YY1, CCAAT binding factor/nuclear factor-Y/Yin Yang 1
OT  - CECs, choroidal endothelial cells
OT  - CNV, choroidal neovascularization
OT  - DCFH-DA, dichlorodihydrofluorescin diacetate
OT  - DMSO, dimethylsulphoxide
OT  - E3330
OT  - Fluc, firefly luciferase
OT  - HIF-1alpha, hypoxia inducible factor-1alpha
OT  - HSF1, heat-shock factor 1
OT  - IkappaB-alpha, inhibitory NF-kappaB-alpha
OT  - MCP-1, monocyte chemoattractant protein-1
OT  - MTF1, metal regulatory transcription factor 1
OT  - NF-kappaB, nuclear factor-kappaB
OT  - Nox, NADPH oxidase
OT  - Nrf, nuclear factor erythroid-2-related factor
OT  - Oxidative stress
OT  - RNV, retinal neovascularization
OT  - ROS, reactive oxygen species
OT  - RPE, retinal pigment epithelium
OT  - RVECs, retinal vascular endothelial cells
OT  - Retinal pigment epithelial cell
OT  - Rluc, renilla luciferase
OT  - SA-beta-gal, senescence associated beta-gal
OT  - SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis
OT  - TUNEL, TdT mediated dUTP-fluorescein nick end-labeling
OT  - Transcription factor
OT  - VEGF, vascular endothelial growth factor
OT  - oxLDL, oxidized low density lipoprotein
OT  - redox, reduction/oxidation
EDAT- 2014/03/14 06:00
MHDA- 2014/03/14 06:01
PMCR- 2014/02/21
CRDT- 2014/03/14 06:00
PHST- 2013/12/16 00:00 [received]
PHST- 2014/01/29 00:00 [revised]
PHST- 2014/01/31 00:00 [accepted]
PHST- 2014/03/14 06:00 [entrez]
PHST- 2014/03/14 06:00 [pubmed]
PHST- 2014/03/14 06:01 [medline]
PHST- 2014/02/21 00:00 [pmc-release]
AID - S2213-2317(14)00038-X [pii]
AID - 10.1016/j.redox.2014.01.023 [doi]
PST - epublish
SO  - Redox Biol. 2014 Feb 21;2:485-94. doi: 10.1016/j.redox.2014.01.023. eCollection 
      2014.