Intracelluláris védekező mechanizmusok akut pancreatitisben: kísérletes és klinikai vizsgálatok = Intracellular protective mechanisms in acute pancreatitis: experimental and clinical investigations

● Arginin (Arg)-indukálta kísérletes pancreatitis során az Arg specifikus és dózis-függő NF-kB aktivációt okoz. ● Pyrrolidin dithiocarbamáttal és steroidokkal végzett előkezelés blokkolja az NF-kB aktivációt, és csökkenti a pancreatitis intenzitását. A steroid receptor antagonista RU-38486 fokozta a pancreatitis indukálta gyulladásos jeleket. ● Szintetikus NF-kB gátló peptidet (PN50) ill. azt a sejtbe transzportáló penetratin analógot állítottunk elő, melyek alkalmazásával az elő- és utókezelés egyaránt jelentősen csökkentette a cholecystokinin (CCK)-indukálta kísérletes pancreatitis súlyosságát. ● A szintetikus proteoszóma inhibitor MG132 tripeptid jelentősen gátolta az IkB degradációt és a következményes NF-kB aktivációt. Ez a magyarázata annak, hogy az MG132-vel végzett elő- és utókezelés egyaránt jelentősen csökkentette a CCK-indukálta kísérletes pancreatitis súlyosságát. ● Ischemia-reperfúzióval kiváltott nekrotizáló pancreatitis kialakulásában igazoltuk a gyulladásos cytokinek, és a nitrogén monoxid szerepét, és azt, hogy az apoptosis fokozásával mérsékelhető a necrosis mértéke. ● Genetikai eredményeink arra utalnak, hogy a humán acut pancreatitis súlyosságát a CD14 LPS receptor polymorfizmusa nem befolyásolja. A HSP70-2G és a TNF-?-308 allélek előfordulása azonban jelentősen gyakoribb volt a súlyos nekrotizáló formákban. | ● Arginine (Arg) induces a dose-dependent activation of NF-kB in Arg-induced pancreatitis. ● Both pyrrolidin dithiocarbamate (PDTC) and steroid pretreatment blocked the activation of NF-kB with simultaneous decrease in the intensity of the inflammation. The steroid receptor antagonist RU-38486 had an opposite effect. ● Both the synthetic inhibitory peptide (PN50) of NF-kB and the cell transporter penetratin significantly decreased the severity of CCK-induced experimental pancreatitis. As sign of cyto-protection, PN50 increased the proportion of apoptosis versus necrosis of acinar cells. ● The synthetic proteasome inhibitor MG132 tripeptide (Z-Leu-Leu-Leu-aldehyd) significantly inhibited the degradation of IkB and the activation of NF-kB. ● Melatonin and resveratrol diminished severity and mortality of pancreatitis. ● In human studies we have demonstrated that high frequencies of the HSP70-2 G and the TNF-?-308 alleles were associated with risk of severe acute pancreatitis. Genotype assessments with determination of the polymorphisms of these genes may be important prognostic tools to predict disease severity and the course of acute pancreatitis. ● Pancreatic ductal epithelium derived from guinea pig was infected with genetically modified (non-virulent) pseudorabies virus. These results may open the possibility for gene transfer and gene therapy of the pancreas

Assessment of cardiometabolic risk among shift workers in Hungary

Aim: Shift workers may be at risk of different diseases. In order to assess cardiometabolic risk in shift workers, a cross-sectional study was performed among active workers. Methods: A total of 481 workers (121 men, 360 women) were investigated; most of them were employees in light industry (58.2%) or in public services (23.9%). Past medical history was recorded and physical examination was performed. Questionnaires were used to characterize daily activity. Fasting venous blood sample was collected for measuring laboratory parameters. Data from shift workers (n = 234, age: 43.9 ± 8.1 years) were compared to those of daytime workers (n = 247, age: 42.8 ± 8.5 years), men and women were analyzed separately. Results: In men, systolic blood pressure was higher in shift workers compared to daytime workers (133 ± 8 vs 126 ± 17 mmHg; p < 0.05). In women, weight (73.6 ± 15.5 vs 67.7 ± 13.2 kg; p < 0.001), body mass index (27.5 ± 5.7 vs 25.0 ± 4.3 kg/m2; p<0.001) and the prevalence rate of hypertension in the past medical history (24.4 vs 13.4%; p < 0.01) were higher in shift workers compared to daytime workers. In addition, the proportion of current smokers was higher (37.7 vs 21.7%; p < 0.001) and HDL-cholesterol level was lower (1.56 ± 0.32 vs 1.68 ± 0.36 mmol/l; p < 0.01) in female shift workers than in female daytime workers. Both in men and in women, rotating shift workers spent less time sleeping both on working days and on non-working days, spent less time with sport activity, drank more coffee and they spent less tim

Effect of melatonin on the severity of l-arginine-induced experimental acute pancreatitis in rats

AIM: To determine the effect of melatonin pre- and post-treatment on the severity of L-arginine (L-Arg) -induced experimental pancreatitis in rats. METHODS: Male Wistar rats (25) were divided into five groups. Those in group A received two injections of 3.2g/kg body weight L-Arg i.p. at an interval of 1h. In group MA, the rats were treated with 50 mg/kg body weight melatonin i.p. 30 min prior to L-Arg administration. In group AM, the rats received the same dose of melatonin 1h after L-Arg was given. In group M, a single dose of melatonin was administered as described previously. In group C the control animals received physiological saline injections i.p. All rats were exsanguinated 24 h after the second L-Arg injection. RESULTS: L-Arg administration caused severe necrotizing pancreatitis confirmed by the significant elevations in the serum amylase level, the pancreatic weight/body weight ratio (pw/bw), the pancreatic IL-6 content and the myeloperoxidase activity, relative to the control values. Elevation of the serum amylase level was significantly reduced in rats given melatonin following L-Arg compared to rats injected with L-Arg only. The activities of the pancreatic antioxidant enzymes (Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and catalase (CAT)) were significantly increased 24 h after pancreatitis induction. Melatonin given in advance of L-Arg significantly reduced the pancreatic CAT activity relative to that in the rats treated with L-Arg alone. In the liver, L-Arg significantly increased the lipid peroxidation level, and the glutathione peroxidase and Cu/Zn-SOD activities, whereas the Mn-SOD activity was reduced as compared to the control rats. Melatonin pre-treatment prevented these changes. CONCLUSION: Melatonin is an antioxidant that is able to counteract some of the L-Arg-induced changes during acute pancreatitis, and may therefore be helpful in the supportive therapy of patients with acute necrotizing pancreatitis

A nuclear import inhibitory peptide ameliorates the severity of cholecystokinin-induced acute pancreatitis

AIM: 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. CONCLUSION: 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