title: Melatonin metabolite, N(1)-acetyl-N(1)-formyl-5-methoxykynuramine (AFMK), attenuates acute pancreatitis in the rat: in vivo and in vitro studies.
abstract: Melatonin protects the pancreas from inflammation and free radical damage but the effect of the melatonin metabolite: N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) on acute pancreatitis is unknown. This study assessed the effects of AFMK on acute pancreatitis (AP) in the rats in vivo and on pancreatic cell line AR42J in vitro. AFMK (5, 10 or 20 mg/kg) was given intraperitoneally to the rats 30 min prior to the induction of AP by subcutaneous caerulein infusion (25 μg/kg). Lipid peroxidation products (MDA + 4-HNE) and the activity of an antioxidant enzyme glutathione peroxidase (GPx) were measured in pancreatic tissue. Blood samples were taken for evaluation of amylase activity and TNF-α concentration. GPx, TNF-α, proapoptotic Bax protein, antiapoptotic Bcl-2 protein and the executor of apoptosis, caspase-3, were determined by Western blot in AR42J cells subjected to AFMK or to melatonin (both used at 10(-12), 10(-10), or 10(-8)M), without or with addition of caerulein (10(-8)M). AP was confirmed by histological examination and by serum increases of amylase and TNF-α (by 800% and 300%, respectively). In AP rats, pancreatic MDA + 4-HNE levels were increased by 300%, whereas GPx was reduced by 50%. AFMK significantly diminished histological manifestations of AP, decreased serum amylase activity and TNF-α concentrations, reduced MDA + 4-HNE levels and augmented GPx in the pancreas of AP rats. In AR42J cells, AFMK combined with caerulein markedly increased protein signals for GPx, Bax, caspase-3 and reduced these for TNF-α and Bcl-2. In conclusion, AFMK significantly attenuated acute pancreatitis in the rat. This may relate to the antioxidative and anti-inflammatory effects of this molecule and possibly to the stimulation of proapoptotic signal transduction pathway.
authors: Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland. jolanta.jaworek@uj.edu.pl.
authors: J
authors: J
authors: Jaworek
authors: Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland.
authors: J
authors: J
authors: Szklarczyk
authors: Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland.
authors: J
authors: J
authors: Bonior
authors: Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland.
authors: M
authors: M
authors: Kot
authors: Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland.
authors: M
authors: M
authors: Goralska
authors: Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland.
authors: P
authors: P
authors: Pierzchalski
authors: Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA.
authors: R J
authors: RJ
authors: Reiter
authors: Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland.
authors: U
authors: U
authors: Czech
authors: Department of Pathomorphology, Medical Faculty Jagiellonian University Medical College, Cracow, Poland.
authors: R
authors: R
authors: Tomaszewska
mesh_terms: D000208:Acute Disease; D000447:Aldehydes / Q000378:metabolism; D000681:Amylases / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D005979:Glutathione Peroxidase / Q000378:metabolism; D007735:Kynuramine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008550:Melatonin / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; C494828:Bax protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D007735:Kynuramine; D008315:Malondialdehyde; C041550:N-acetyl-N-formyl-5-methoxykynurenamine; D005979:Glutathione Peroxidase; D000681:Amylases; C505410:Casp3 protein, rat; D053148:Caspase 3; D008550:Melatonin; C027576:4-hydroxy-2-nonenal