PMID- 29270134
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 1664-042X (Print)
IS  - 1664-042X (Electronic)
IS  - 1664-042X (Linking)
VI  - 8
DP  - 2017
TI  - Novel Small Molecule Inhibitors of Protein Kinase D Suppress NF-kappaB Activation 
      and Attenuate the Severity of Rat Cerulein Pancreatitis.
PG  - 1014
LID - 10.3389/fphys.2017.01014 [doi]
LID - 1014
AB  - Nuclear factor-kappa B (NF-kappaB) activation is a key early signal regulating 
      inflammatory and cell death responses in acute pancreatitis. Our previous in 
      vitro studies with molecular approaches on AR42J cell showed that protein kinase 
      D (PKD/PKD1) activation was required in NF-kappaB activation induced by 
      cholecystokinin 8 (CCK) or carbachol (CCh) in pancreatic acinar cells. Recently 
      developed small molecule PKD inhibitors, CID755673 and CRT0066101, provide 
      potentially important pharmacological approaches to further investigate the 
      effect of PKD in pancreatitis therapy. The aim of this study was to explore 
      whether CID755673 and CRT0066101 block NF-kappaB activation with in vitro and in vivo 
      models of experimental pancreatitis and whether the small molecule PKD inhibitors 
      have therapeutic effects when given before or after the initiation of 
      experimental pancreatitis. Freshly prepared pancreatic acini were incubated with 
      CID755673 or CRT006101, followed by hyperstimulation with CCK or CCh. For in vivo 
      experimental pancreatitis, rats were treated with intraperitoneal injection of 
      CID755673 or CRT0066101 prior to or after administering cerulein or saline. PKD 
      activation and NF-kappaB-DNA binding activity in nuclear extracts from pancreatic 
      acini and tissue were measured. The effects of PKD inhibitors on pancreatitis 
      responses were evaluated. Our results showed that both CID755673 or CRT0066101 
      selectively and specifically inhibited PKD without effects on related protein 
      kinase Cs. Inhibition of PKD resulted in significantly attenuation of NF-kappaB 
      activation in both in vitro and in vivo models of experimental pancreatitis. 
      NF-kappaB inhibition by CID755673 was associated with decreased inflammatory 
      responses and attenuated severity of the disease, which were indicated by less 
      inflammatory cell infiltration, reduced pancreatic interleukin-6 (IL-6) and 
      monocyte chemoattractant protein-1 (MCP-1), decreased intrapancreatic trypsin 
      activation, and alleviation in pancreatic necrosis, edema and vacuolization. 
      Furthermore, PKD inhibitor CID755673, given after the initiation of pancreatitis 
      in experimental rat model, significantly attenuated the severity of acute 
      pancreatitis. Therapies for acute pancreatitis are limited. Our results indicate 
      that small chemical PKD inhibitors have significant potential as therapeutic 
      interventions by suppressing NF-kappaB activation.
FAU - Yuan, Jingzhen
AU  - Yuan J
AD  - Cedars-Sinai Medical Center, Los Angeles, CA, United States.
AD  - Veterans Affairs Greater Los Angeles Healthcare System, Department of Medicine, 
      University of California, Los Angeles, Los Angeles, CA, United States.
FAU - Tan, Tanya
AU  - Tan T
AD  - Veterans Affairs Greater Los Angeles Healthcare System, Department of Medicine, 
      University of California, Los Angeles, Los Angeles, CA, United States.
AD  - Georgetown University Medical Center, Washington, DC, United States.
FAU - Geng, Meng
AU  - Geng M
AD  - Veterans Affairs Greater Los Angeles Healthcare System, Department of Medicine, 
      University of California, Los Angeles, Los Angeles, CA, United States.
AD  - Frank Netter H. School of Medicine at Quinnipiac University, Hamden, CT, United 
      States.
FAU - Tan, Grace
AU  - Tan G
AD  - Veterans Affairs Greater Los Angeles Healthcare System, Department of Medicine, 
      University of California, Los Angeles, Los Angeles, CA, United States.
AD  - Vanderbilt University, Nashville, TN, United States.
FAU - Chheda, Chintan
AU  - Chheda C
AD  - Cedars-Sinai Medical Center, Los Angeles, CA, United States.
FAU - Pandol, Stephen J
AU  - Pandol SJ
AD  - Cedars-Sinai Medical Center, Los Angeles, CA, United States.
AD  - Veterans Affairs Greater Los Angeles Healthcare System, Department of Medicine, 
      University of California, Los Angeles, Los Angeles, CA, United States.
LA  - eng
GR  - P01 DK098108/DK/NIDDK NIH HHS/United States
GR  - P30 DK041301/DK/NIDDK NIH HHS/United States
GR  - P50 AA011999/AA/NIAAA NIH HHS/United States
GR  - R01 AA024464/AA/NIAAA NIH HHS/United States
PT  - Journal Article
DEP - 20171207
PL  - Switzerland
TA  - Front Physiol
JT  - Frontiers in physiology
JID - 101549006
PMC - PMC5725929
OTO - NOTNLM
OT  - NF-kappaB
OT  - PKD inhibitors
OT  - pancreatitis
OT  - protein kinase D
EDAT- 2017/12/23 06:00
MHDA- 2017/12/23 06:01
PMCR- 2017/12/07
CRDT- 2017/12/23 06:00
PHST- 2017/08/29 00:00 [received]
PHST- 2017/11/22 00:00 [accepted]
PHST- 2017/12/23 06:00 [entrez]
PHST- 2017/12/23 06:00 [pubmed]
PHST- 2017/12/23 06:01 [medline]
PHST- 2017/12/07 00:00 [pmc-release]
AID - 10.3389/fphys.2017.01014 [doi]
PST - epublish
SO  - Front Physiol. 2017 Dec 7;8:1014. doi: 10.3389/fphys.2017.01014. eCollection 
      2017.