A nuclear import inhibitory peptide ameliorates the severity of cholecystokinin-induced acute pancreatitis.
OBJECTIVE
To assess the effect of our novel cell-permeable nuclear factor-kappaB (NF-kappaB) inhibitor peptide PN50 in an experimental model of acute pancreatitis. PN50 was produced by conjugating the cell-penetrating penetratin peptide with the nuclear localization signal of the NF-kappaB p50 subunit.


METHODS
Pancreatitis was induced in male Wistar rats by administering 2X100 mug/kg body weight of cholecystokinin-octapeptide (CCK) intraperitoneally (IP) at an interval of 1 h. PN50-treated animals received 1 mg/kg of PN50 IP 30 min before or after the CCK injections. The animals were sacrificed 4 h after the first injection of CCK.


RESULTS
All the examined laboratory (the pancreatic weight/body weight ratio, serum amylase activity, pancreatic levels of TNF-alpha and IL-6, degree of lipid peroxidation, reduced glutathione levels, NF-kappaB binding activity, pancreatic and lung myeloperoxidase activity) and morphological parameters of the disease were improved before and after treatment with the PN50 peptide. According to the histological findings, PN50 protected the animals against acute pancreatitis by favoring the induction of apoptotic, as opposed to necrotic acinar cell death associated with severe acute pancreatitis.


CONCLUSIONS
Our study implies that reversible inhibitors of stress-responsive transcription factors like NF-kappaB might be clinically useful for the suppression of the severity of acute pancreatitis.
Letoha
Tamas
T
Department of Medical Chemistry, University of Szeged, Domter 8, H-6720 Szeged, Hungary. tletoha@yahoo.com
Somlai
Csaba
C
Takacs
Tamas
T
Szabolcs
Annamaria
A
Jarmay
Katalin
K
Rakonczay
Zoltan
Z
Hegyi
Peter
P
Varga
Ilona
I
Kaszaki
Jozsef
J
Krizbai
Istvan
I
Boros
Imre
I
Duda
Erno
E
Kusz
Erzsebet
E
Penke
Botond
B
D021581:Active Transport, Cell Nucleus; D000208:Acute Disease; D000595:Amino Acid Sequence; D000681:Amylases / Q000097:blood; D000818:Animals; D001835:Body Weight; D002461:Cell Line, Transformed; D024202:Electrophoretic Mobility Shift Assay; D005978:Glutathione / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009929:Organ Size; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D010455:Peptides / Q000235:genetics / Q000493:pharmacokinetics*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012844:Sincalide; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D016328:NF-kappa B; D010455:Peptides; C118258:SN50 peptide; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D000681:Amylases; D005978:Glutathione; D012844:Sincalide
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