PMID- 29627323
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210109
IS  - 1879-2642 (Electronic)
IS  - 0005-2736 (Print)
IS  - 0005-2736 (Linking)
VI  - 1860
IP  - 9
DP  - 2018 Sep
TI  - Apoptosis signal regulating kinase-1 and NADPH oxidase mediate human amylin 
      evoked redox stress and apoptosis in pancreatic beta-cells.
PG  - 1721-1733
LID - S0005-2736(18)30104-4 [pii]
LID - 10.1016/j.bbamem.2018.03.024 [doi]
AB  - Misfolded toxic human islet amyloid polypeptide or amylin (hA) and plasma 
      membrane-associated redox complex, NADPH oxidase (NOX), have been implicated in 
      the islet beta-cell demise associated with type-2 diabetes mellitus (T2DM). Studies 
      show that hA accumulation is stressful to beta-cells and that misfolding of human 
      amylin evokes redox stress and activates mitogen activated protein (MAP) kinases, 
      p38 MAPK and c-Jun N-terminal (JNK) kinase. However, the molecular link and 
      causality between hA-evoked redox stress, NOX activity and MAP kinases signaling 
      in pancreatic beta-cells is incompletely understood. Here, we show that in the 
      process of activating JNK, aggregation prone hA also activates an upstream 
      apoptosis signal regulating kinase-1 (ASK1) with concomitant decrease in 
      intracellular levels of reduced glutathione. Inhibition of ASK1 kinase activity, 
      either by specific ASK1 inhibitor, NQDI1 or by thiol antioxidants reduces human 
      amylin-evoked ASK1 and JNK activation and consequently human amylin toxicity in 
      rat insulinoma Rin-m5F cells and human islets. beta-cell specific overexpression of 
      human amylin in mouse islets elicited ASK1 phosphorylation and activation in 
      beta-cells but not in other rodent's islet or exocrine cells. This ASK1 activation 
      strongly correlated with islet amyloidosis and diabetes progression. Cytotoxic 
      human amylin additionally stimulated pro-oxidative activity and expressions of 
      plasma membrane bound NADPH oxidase (NOX) and its regulatory subunits. siRNA 
      mediated NOX1 knockdown and selective NOX inhibitors, ML171 and apocynin, 
      significantly reduced hA-induced mitochondrial stress in insulinoma beta-cells. 
      However, NOX inhibitors were largely ineffective against hA-evoked redox stress 
      and activation of cytotoxic ASK1/JNK signaling complex. Thus, our studies suggest 
      that NOX1 and ASK1 autonomously mediate human amylin-evoked redox and 
      mitochondrial stress in pancreatic beta-cells.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Singh, Sanghamitra
AU  - Singh S
AD  - Department of Biological Sciences, The George Washington University, Washington, 
      DC 20052, USA.
FAU - Bhowmick, Diti Chatterjee
AU  - Bhowmick DC
AD  - Department of Biological Sciences, The George Washington University, Washington, 
      DC 20052, USA.
FAU - Pany, Satyabrata
AU  - Pany S
AD  - Department of Biological Sciences, The George Washington University, Washington, 
      DC 20052, USA.
FAU - Joe, Myungkuk
AU  - Joe M
AD  - Department of Biological Sciences, The George Washington University, Washington, 
      DC 20052, USA.
FAU - Zaghlula, Noor
AU  - Zaghlula N
AD  - Department of Biological Sciences, The George Washington University, Washington, 
      DC 20052, USA.
FAU - Jeremic, Aleksandar M
AU  - Jeremic AM
AD  - Department of Biological Sciences, The George Washington University, Washington, 
      DC 20052, USA. Electronic address: jerema@gwu.edu.
LA  - eng
GR  - R01 DK091845/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20180406
PL  - Netherlands
TA  - Biochim Biophys Acta Biomembr
JT  - Biochimica et biophysica acta. Biomembranes
JID - 101731713
SB  - IM
PMC - PMC6177334
MID - NIHMS957848
OTO - NOTNLM
OT  - ASK-1 kinase
OT  - Human amylin
OT  - Human islets
OT  - NADPH oxidase
OT  - Oxidative stress
OT  - Plasma membrane
OT  - Type-2 diabetes mellitus
EDAT- 2018/04/09 06:00
MHDA- 2018/04/09 06:01
PMCR- 2019/10/06
CRDT- 2018/04/09 06:00
PHST- 2017/12/30 00:00 [received]
PHST- 2018/03/22 00:00 [revised]
PHST- 2018/03/24 00:00 [accepted]
PHST- 2018/04/09 06:00 [pubmed]
PHST- 2018/04/09 06:01 [medline]
PHST- 2018/04/09 06:00 [entrez]
PHST- 2019/10/06 00:00 [pmc-release]
AID - S0005-2736(18)30104-4 [pii]
AID - 10.1016/j.bbamem.2018.03.024 [doi]
PST - ppublish
SO  - Biochim Biophys Acta Biomembr. 2018 Sep;1860(9):1721-1733. doi: 
      10.1016/j.bbamem.2018.03.024. Epub 2018 Apr 6.