PMID- 28253732
OWN - NLM
STAT- MEDLINE
DCOM- 20180312
LR  - 20220321
IS  - 1557-7716 (Electronic)
IS  - 1523-0864 (Print)
IS  - 1523-0864 (Linking)
VI  - 27
IP  - 14
DP  - 2017 Nov 10
TI  - The Indirubin Derivative 6-Bromoindirubin-3'-Oxime Activates Proteostatic 
      Modules, Reprograms Cellular Bioenergetic Pathways, and Exerts Antiaging Effects.
PG  - 1027-1047
LID - 10.1089/ars.2016.6910 [doi]
AB  - AIMS: Organismal aging can be delayed by mutations that either activate stress 
      responses or reduce the nutrient-sensing pathway signaling; thus, by using 
      Drosophila melanogaster as an in vivo experimental screening platform, we 
      searched for compounds that modulate these pathways. RESULTS: We noted that oral 
      administration of the glycogen synthase kinase 3 (Gsk-3) inhibitor 
      6-bromoindirubin-3'-oxime (6BIO) in Drosophila flies extended healthy life span. 
      6BIO is not metabolized in fly tissues, modulated bioenergetic pathways, 
      decreased lipid and glucose tissue load, activated antioxidant and proteostatic 
      modules, and enhanced resistance to stressors. Mechanistically, we found that the 
      effects on the stress-responsive pathways were largely dependent on the activity 
      of the transcription factor nuclear factor erythroid 2-related factor (Nrf-2). 
      Genetic inhibition of Gsk-3 largely phenocopied the 6BIO-mediated effects, while 
      high levels of Gsk-3 expression and/or kinase activity suppressed proteostatic 
      modules and reduced flies' longevity; these effects were partially rescued by 
      6BIO. Also, 6BIO was found to partially reduce the 3-phosphoinositide-dependent 
      protein kinase-1 (Pdpk1) activity, a major effector of the insulin/insulin-like 
      growth factor-1 cell signaling pathways. INNOVATION: 6BIO exerts the unique 
      property of increasing stress tolerance and in parallel partially suppressing the 
      nutrient-sensing pathway signaling. CONCLUSION: Our findings suggest that the 
      6BIO scaffold can be used for the development of novel antiaging compounds. 
      Antioxid. Redox Signal. 27, 1027-1047.
FAU - Tsakiri, Eleni N
AU  - Tsakiri EN
AD  - 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and 
      Kapodistrian University of Athens , Athens, Greece .
FAU - Gaboriaud-Kolar, Nicolas
AU  - Gaboriaud-Kolar N
AD  - 2 Department of Pharmacognosy and Natural Products Chemistry, Faculty of 
      Pharmacy, National and Kapodistrian University of Athens , Athens, Greece .
FAU - Iliaki, Kalliopi K
AU  - Iliaki KK
AD  - 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and 
      Kapodistrian University of Athens , Athens, Greece .
FAU - Tchoumtchoua, Job
AU  - Tchoumtchoua J
AD  - 2 Department of Pharmacognosy and Natural Products Chemistry, Faculty of 
      Pharmacy, National and Kapodistrian University of Athens , Athens, Greece .
FAU - Papanagnou, Eleni-Dimitra
AU  - Papanagnou ED
AD  - 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and 
      Kapodistrian University of Athens , Athens, Greece .
FAU - Chatzigeorgiou, Sofia
AU  - Chatzigeorgiou S
AD  - 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and 
      Kapodistrian University of Athens , Athens, Greece .
FAU - Tallas, Konstantinos D
AU  - Tallas KD
AD  - 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and 
      Kapodistrian University of Athens , Athens, Greece .
FAU - Mikros, Emmanuel
AU  - Mikros E
AD  - 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and 
      Kapodistrian University of Athens , Athens, Greece .
FAU - Halabalaki, Maria
AU  - Halabalaki M
AD  - 2 Department of Pharmacognosy and Natural Products Chemistry, Faculty of 
      Pharmacy, National and Kapodistrian University of Athens , Athens, Greece .
FAU - Skaltsounis, Alexios-Leandros
AU  - Skaltsounis AL
AD  - 2 Department of Pharmacognosy and Natural Products Chemistry, Faculty of 
      Pharmacy, National and Kapodistrian University of Athens , Athens, Greece .
FAU - Trougakos, Ioannis P
AU  - Trougakos IP
AD  - 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and 
      Kapodistrian University of Athens , Athens, Greece .
LA  - eng
PT  - Journal Article
DEP - 20170516
PL  - United States
TA  - Antioxid Redox Signal
JT  - Antioxidants & redox signaling
JID - 100888899
RN  - 0 (6-bromoindirubin-3'-oxime)
RN  - 0 (Drosophila Proteins)
RN  - 0 (Indoles)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Oximes)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Administration, Oral
MH  - Aging/*drug effects/metabolism
MH  - Animals
MH  - Disease Models, Animal
MH  - Drosophila Proteins/metabolism
MH  - Drosophila melanogaster/*drug effects/metabolism
MH  - Energy Metabolism/*drug effects
MH  - Female
MH  - Glycogen Synthase Kinase 3/metabolism
MH  - Humans
MH  - Indoles/*administration & dosage/pharmacology
MH  - Male
MH  - Metabolic Networks and Pathways/drug effects
MH  - NF-E2-Related Factor 2/metabolism
MH  - Oximes/*administration & dosage/pharmacology
MH  - Proteostasis/*drug effects
PMC - PMC5651956
OTO - NOTNLM
OT  - 6-bromoindirubin-3'-oxime
OT  - Gsk-3
OT  - Nrf-2
OT  - Pdpk1
OT  - aging
OT  - proteostasis
COIS- No competing financial interests exist.
EDAT- 2017/03/04 06:00
MHDA- 2018/03/13 06:00
PMCR- 2017/11/10
CRDT- 2017/03/04 06:00
PHST- 2017/03/04 06:00 [pubmed]
PHST- 2018/03/13 06:00 [medline]
PHST- 2017/03/04 06:00 [entrez]
PHST- 2017/11/10 00:00 [pmc-release]
AID - 10.1089/ars.2016.6910 [pii]
AID - 10.1089/ars.2016.6910 [doi]
PST - ppublish
SO  - Antioxid Redox Signal. 2017 Nov 10;27(14):1027-1047. doi: 10.1089/ars.2016.6910. 
      Epub 2017 May 16.