PMID- 37063699
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240112
IS  - 1934-578X (Print)
IS  - 1555-9475 (Electronic)
IS  - 1555-9475 (Linking)
VI  - 18
IP  - 1
DP  - 2023 Jan
TI  - Indirubin Inhibits TRAIL-Induced Activation of Death Receptor 5 in Jurkat Cells.
LID - 10.1177/1934578x221144580 [doi]
AB  - Death receptor 5 (DR5) is an apoptosis-inducing membrane receptor that mediates 
      cell death in several life-threatening conditions. There is a crucial need for 
      the discovery of DR5 antagonists for the therapeutic intervention of conditions 
      in which the overactivation of DR5 underlies the pathophysiology. DR5 activation 
      mediates cell death in non-alcoholic fatty liver disease (NAFLD) and 
      neurodegenerative processes including amyloid-beta (Abeta) accumulation, spinal cord 
      injury (SCI), and brain ischemia. In the current work, we used fluorescence 
      resonance energy transfer (FRET) to monitor the conformational dynamics of DR5 
      that mediate death signaling. We used a time-resolved FRET screening platform to 
      screen the Selleck library of 2863 U.S. Food and Drug Administration 
      (FDA)-approved compounds. The high-throughput screen (HTS) identified 13 
      compounds that modulated the FRET between DR5 monomers beyond 5 median absolute 
      deviations (MADs) from the DMSO controls. Of these 13 compounds, indirubin was 
      identified to specifically inhibit tumor necrosis factor-related 
      apoptosis-inducing ligand (TRAIL)-induced caspase-8 activity without modulating 
      DR5 surface expression or TRAIL binding. Indirubin inhibited Fas-associated death 
      domain (FADD) oligomerization and increased cellular FLICE-inhibitory protein 
      (c-FLIP) expression; both are molecular mechanisms involved in inhibiting the DR5 
      signaling cascade. This study has elucidated previously unknown properties of 
      indirubin that make it a promising candidate for therapeutic investigation of 
      diseases in which overactivation of DR5 underlies pathology.
FAU - Young, Malaney C
AU  - Young MC
AUID- ORCID: 0000-0001-5857-2851
AD  - Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, 
      USA.
FAU - Vunnam, Nagamani
AU  - Vunnam N
AD  - Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, 
      USA.
FAU - Rebbeck, Robyn T
AU  - Rebbeck RT
AD  - Department of Biochemistry, Molecular Biology, and Biophysics, University of 
      Minnesota, Minneapolis, MN, USA.
FAU - Yuen, Samantha L
AU  - Yuen SL
AD  - Department of Biochemistry, Molecular Biology, and Biophysics, University of 
      Minnesota, Minneapolis, MN, USA.
FAU - Thomas, David D
AU  - Thomas DD
AD  - Department of Biochemistry, Molecular Biology, and Biophysics, University of 
      Minnesota, Minneapolis, MN, USA.
FAU - Sachs, Jonathan N
AU  - Sachs JN
AD  - Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, 
      USA.
LA  - eng
GR  - R01 HL139065/HL/NHLBI NIH HHS/United States
GR  - R35 GM131814/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20230111
PL  - United States
TA  - Nat Prod Commun
JT  - Natural product communications
JID - 101477873
PMC - PMC10100512
MID - NIHMS1876409
OTO - NOTNLM
OT  - TRAIL
OT  - alkaloid
OT  - death receptor 5
OT  - high-throughput screening
OT  - indirubin
COIS- Declaration of Conflicting Interests The author(s) declared no potential 
      conflicts of interest with respect to the research, authorship, and/or 
      publication of this article.
EDAT- 2023/04/18 06:00
MHDA- 2023/04/18 06:01
PMCR- 2024/01/11
CRDT- 2023/04/17 03:33
PHST- 2023/04/18 06:01 [medline]
PHST- 2023/04/17 03:33 [entrez]
PHST- 2023/04/18 06:00 [pubmed]
PHST- 2024/01/11 00:00 [pmc-release]
AID - 10.1177/1934578x221144580 [doi]
PST - ppublish
SO  - Nat Prod Commun. 2023 Jan;18(1):10.1177/1934578x221144580. doi: 
      10.1177/1934578x221144580. Epub 2023 Jan 11.