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ABSTRACT: The proteosome inhibitor bortezomib is used in the treatment of patients with multiple myeloma. Proteosomes are responsible for the degradation of I-kappaB, the inhibitory protein of transcription factor nuclear factor kappa B (Nf-kappaB). The heat shock protein (HSP) inducing effect of bortezomib is also documented. The aim of our work was to test the anti-inflammatory effect of bortezomib in cholecystokinin-octapeptide (CCK-8)-induced acute pancreatitis. Male Wistar rats were divided into three groups (n=8 in each). Group P received an i.p. injection of physiological saline (p.s.) 60 min. before the induction of acute pancreatitis by three hourly s.c. injections of 100 microg/kg CCK-8. Group BP received 1 mg/kg bortezomib dissolved in p.s. 1 h previous to pancreatitis induction. Group C was treated with the vehicle (p.s.). Animals were exsanguinated 4 h after the last injection of CCK-8. Bortezomib pre-treatment significantly reduced the pancreatic weight/body weight ratio, and improved the histology by decreasing the extent of vacuolization and infiltration. Bortezomib pre-treatment inhibited I-kappaBbeta degradation, and induced the synthesis of HSP72. The results confirmed the anti-inflammatory effect of bortezomib in acute experimental pancreatitis. This effect of the drug is presumably mediated by the inhibition of Nf-kappaB activation and induction of HSP synthesis.
European journal of pharmacology 06/2009; 616(1-3):270-4. · 2.59 Impact Factor
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ABSTRACT: To investigate the consequences of treatment with an exogenous glucocorticoid agonist (methylprednisolone) and antagonist (RU-38486) on the local and systemic responses in L-arginine-induced acute pancreatitis in rats.
The methylprednisolone and RU-38486 were administered just before pancreatitis induction. Plasma amylase activity, interleukin 6 activity, pancreatic weight/body weight ratio, plasma macrophage migration inhibitory factor (MIF) concentration, and pancreatic nuclear transcription factor (NF) kappaB activity were determined. The extents of pancreas, liver, and lung injuries were assessed by histology.
Acute pancreatitis resulted in NF-kappaB activation and proinflammatory cytokine release in rats. In the glucocorticoid agonist group, plasma amylase and interleukin 6 levels were significantly decreased as compared with those of RU-38486 and nontreated groups. Antagonist treatment led to significantly higher MIF production at 8 and 12 hours after L-arginine injection as compared with the agonist-treated and nontreated groups. Glucocorticoid agonist treatment significantly decreased the level of NF-kappaB 24 hours after pancreatitis induction. Histological investigations showed protective effect of agonist treatment on acute pancreatitis-induced tissue damage in the pancreas and lung.
These results corroborated the importance of MIF in acute pancreatitis. The glucocorticoid-dependent mechanisms seem to play a crucial role in the control of the inflammatory response and tissue damage in L-arginine-induced experimental acute pancreatitis.
Pancreas 06/2008; 36(4):369-76. · 2.39 Impact Factor
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ABSTRACT: Epidemiological data analysis of a tertiary (regional) medical and surgical center. Diagnostic and therapeutic standards of patients with acute pancreatitis have changed significantly in the last few decades. Progress in laboratory and imaging diagnostics and achievements in experimental research resulted in a significant modification of the guidelines related to the care of pancreatitic patients. The aim was to analyse and compare the data of patients with acute pancreatitis treated in 1996 (period I) and 2004 (period II) at the Departments of Internal Medicine and Surgery, University of Szeged, to evaluate the concordance with international guidelines during medical and surgical treatment. RESULTS: The authors analysed the clinical data of 126 and 124 patients, respectively, with acute pancreatitis observed during the two periods. An increase in the incidence of biliary acute pancreatitis, more frequent use of antibiotics, a higher frequency of therapeutic endoscopies (papillotomy and biliary stone extraction), the general application of ultrasonography-guided fine needle aspiration and bacterial culturing in cases of suspected infected necrosis, and higher effectiveness in complex surgical and supportive management of infected necrosis cases were detected in period II. CONCLUSION: Although most of the achievements suggested in international guidelines on medical/endoscopic and surgical treatment of acute pancreatitis have been implemented during the observation period, no significant changes in the morbidity and mortality data of patients were found.
Orvosi Hetilap 05/2008; 149(14):645-54.
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ABSTRACT: Our experiments were designed to investigate the effects of zerumbone pretreatment on cholecystokinin octapeptide (CCK-8)-induced acute pancreatitis in rats.
Male Wistar rats weighing 240 to 280 g were divided into a control group, a group treated with CCK-8, a group receiving 20 mg/kg zerumbone before CCK-8 administration, and a group treated with zerumbone only.
The serum amylase and lipase activities and the pancreatic weight-body weight ratio were significantly reduced by zerumbone pretreatment, but the drug failed to influence the histological parameters of pancreatitis. The anti-inflammatory effects of the drug were manifested in decreases in the cytosolic interleukin 6 and tumor necrosis factor alpha concentrations and an elevation in the I-kappaB concentration, whereas the antioxidant ability of zerumbone was demonstrated by reductions in inducible nitric oxide synthase, Mn- and Cu/Zn-superoxide dismutase activities in the zerumbone-treated rats.
Zerumbone ameliorated the changes of several parameters of acute pancreatitis probably by interfering with I-kappaB degradation, but in the applied dose, it failed to influence the histology of the disease.
Pancreas 11/2007; 35(3):249-55. · 2.39 Impact Factor
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László Czakó, Annamária Szabolcs,
Agota Vajda,
Sándor Csáti,
Viktória Venglovecz,
Zoltán Rakonczay,
Péter Hegyi,
László Tiszlavicz,
Tamás Csont,
Anikó Pósa,
Anikó Berkó,
Csaba Varga,
Szollosiné Varga Ilona,
Imre Boros,
János Lonovics
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ABSTRACT: The aim of the present study was to investigate whether hyperlipidemia can cause acute pancreatitis or alter its severity. Male Wistar rats were fed a 3% cholesterol-enriched diet or a normal diet for 16 weeks. Edematous and necrotizing pancreatitis was induced with 3x75 mug/kg body weight of cholecystokinin s.c. and 2x2 g/kg body weight of L-arginine i.p., respectively, in separate groups of normal and hyperlipidemic rats. The severity of the pancreatitis was assessed. We studied the influence of hyperlipidemia on the formation of oxygen-derived free radicals, endogenous scavengers, nitric oxide synthases (NOS), peroxynitrite (ONOO(-)), heat shock protein 72 (HSP72) and nuclear factor-kappa B (NF-kappaB) activation in the pancreas during acute edematous and necrotizing pancreatitis. Hyperlipidemia did not worsen edematous, but aggravated necrotizing pancreatitis. The cholesterol-enriched diet significantly reduced the catalase and Mn-superoxide dismutase (SOD) and constitutive NOS (cNOS) activities and increased the inducible NOS (iNOS) in the pancreas relative to those in the rats on the normal diet. The pancreatic nitrotyrosine level, as a marker of ONOO(-), and the NF-kappaB DNA-binding activity in the pancreas, were significantly elevated in the cholesterol-fed rats. The pancreatic HSP72 expression during necrotizing pancreatitis was not influenced by the hyperlipidemia. The pancreatic Mn-SOD, Cu, Zn-SOD, glutathione peroxidase, total glutathione and cNOS activities were significantly reduced, while the catalase, iNOS and NF-kappaB DNA-binding activities were significantly increased in the animals with necrotizing pancreatitis on the cholesterol diet as compared with those with pancreatitis and receiving the normal diet. Hyperlipidemia induced with this cholesterol-enriched diet leads to decreases in endogenous scavenger and cNOS activities, results in iNOS and NF-kappaB activation and stimulates ONOO(-) generation in the pancreas, which may be responsible for the aggravation of acute necrotizing pancreatitis.
European Journal of Pharmacology 11/2007; 572(1):74-81. · 2.52 Impact Factor
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ABSTRACT: Penetratin is a cationic cell-penetrating peptide that has been frequently used for the intracellular delivery of polar bioactive compounds. Recent studies have just revealed the major role of polyanionic membrane proteoglycans and cholesterol-enriched lipid rafts in the uptake of the peptide. Both proteoglycans and lipid-rafts influence inflammatory processes by binding a wide array of proinflammatory mediators; thus, we decided to analyze the effect of penetratin on in vitro and in vivo inflammatory responses. Our in vitro luciferase gene assays demonstrated that penetratin decreased transcriptional activity of nuclear factor-kappaB (NF-kappaB) in tumor necrosis factor (TNF)-stimulated L929 fibroblasts and lipopolysaccharide-activated RAW 264.7 macrophages. Penetratin also inhibited TNF-induced intercellular adhesion molecule-1 expression in human endothelial HMEC-1 cells. Exogenous heparan sulfate abolished the in vitro NF-kappaB inhibitory effects of the peptide. Uptake experiments showed that penetratin was internalized by all of the above-mentioned cell lines in vitro and rapidly entered the cells of the lung and pancreas in vivo. In an in vivo rat model of acute pancreatitis, a disease induced by elevated activities of stress-responsive transcription factors like NF-kappaB, pretreatment with only 2 mg/kg penetratin attenuated the severity of pancreatic inflammation by interfering with IkappaB degradation and subsequent nuclear import of NF-kappaB, inhibiting the expression of proinflammatory genes and improving the monitored laboratory and histological parameters of pancreatitis and associated oxidative stress.
Molecular Pharmacology 07/2006; 69(6):2027-36. · 4.88 Impact Factor
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ABSTRACT: Resveratrol is a phytoalexin with strong antioxidant and anti-inflammatory effects reaching high concentrations in red wine. The aim of our study was to test the effects of resveratrol pretreatment on cholecystokinin-octapeptide (CCK-8)-induced acute pancreatitis in rats. Animals were divided into a control group, a group treated with CCK-8 and a group receiving 10 mg/kg resveratrol prior to CCK-8 administration. Resveratrol ameliorated the CCK-8-induced changes in the laboratory parameters, and reduced the histological damage in the pancreas. The drug failed to improve the pancreatic antioxidant state, but increased the amount of hepatic reduced glutathione and prevented the reduction of hepatic catalase activity. Resveratrol-induced inhibition of nuclear factor kappa B (NF-kappaB) activation or reduction of the pancreatic tumor necrosis factor-alpha (TNF-alpha) concentration could not be demonstrated. In conclusion, the beneficial effects of resveratrol on acute pancreatitis seem to be mediated by the antioxidant effect of resveratrol or by an NF-kappaB-independent anti-inflammatory mechanism.
European Journal of Pharmacology 03/2006; 532(1-2):187-93. · 2.52 Impact Factor
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Tamás Letoha,
Csaba Somlai,
Tamás Takács, Annamária Szabolcs,
Zoltán Rakonczay,
Katalin Jármay,
Tamás Szalontai,
Ilona Varga,
József Kaszaki,
Imre Boros,
Erno Duda,
László Hackler,
István Kurucz,
Botond Penke
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ABSTRACT: The cell-permeant MG132 tripeptide (Z-Leu-Leu-Leu-aldehyde) is a peptide aldehyde proteasome inhibitor that also inhibits other proteases, including calpains and cathepsins. By blocking the proteasome, this tripeptide has been shown to induce the expression of cell-protective heat shock proteins (HSPs) in vitro. Effects of MG132 were studied in an in vivo model of acute pancreatitis. Pancreatitis was induced in male Wistar rats by injecting 2 x 100 microug/kg cholecystokinin octapeptide intraperitoneally (ip) at an interval of 1 h. Pretreating the animals with 10 mg/kg MG132 ip before the induction of pancreatitis significantly inhibited IkappaB degradation and subsequent activation of nuclear factor-kappaB (NF-kappaB). MG132 also increased HSP72 expression. Induction of HSP72 and inhibition of NF-kappaB improved parameters of acute pancreatitis. Thus MG132 significantly decreased serum amylase, pancreatic weight/body weight ratio, pancreatic myeloperoxidase activity, proinflammatory cytokine concentrations, and the expression of pancreatitis-associated protein. Parameters of oxidative stress (GSH, MDA, SOD, etc.) were improved in both the serum and the pancreas. Histopathological examinations revealed that pancreatic specimens of animals pretreated with the peptide demonstrated milder edema, cellular damage, and inflammatory activity. Our findings show that simultaneous inhibition of calpains, cathepsins, and the proteasome with MG132 prevents the onset of acute pancreatitis.
Free Radical Biology and Medicine 12/2005; 39(9):1142-51. · 5.42 Impact Factor
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Péter Hegyi,
Balázs Ordog,
Zoltán Rakonczai,
Tamás Takács,
János Lonovics, Annamária Szabolcs,
Réka Sári,
András Tóth,
Julius-G Papp,
András Varró,
Mária-K Kovács,
Mike-A Gray,
Barry-E Argent,
Zsolt Boldogköi
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ABSTRACT: To examine the effect of acute infection caused by herpesvirus (pseudorabies virus, PRV) on pancreatic ductal secretion.
The virulent Ba-DupGreen (BDG) and non-virulent Ka-RREp0lacgfp (KEG) genetically modified strains of PRV were used in this study and both of them contain the gene for green fluorescent protein (GFP). Small intra/interlobular ducts were infected with BDG virus (10(7) PFU/mL for 6 h) or with KEG virus (10(10) PFU/mL for 6 h), while non-infected ducts were incubated only with the culture media. The ducts were then cultured for a further 18 h. The rate of HCO(3)(-) secretion (base efflux -J(B-)) was determined from the buffering capacity of the cells and the initial rate of intracellular acidification (1) after sudden blockage of basolateral base loaders with dihydro-4,4-diisothiocyanatostilbene-2,2-disulfonic acid (500 micromol/L) and amiloride (200 micromol/L), and (2) after alkali loading the ducts by exposure to NH(4)Cl. All the experiments were performed in HCO(3)(-)-buffered Ringer solution at 37 degrees (n = 5 ducts for each experimental condition). Viral structural proteins were visualized by immunohistochemistry. Virally-encoded GFP and immunofluorescence signals were recorded by a confocal laser scanning microscope.
The BDG virus infected the majority of accessible cells of the duct as judged by the appearance of GFP and viral antigens in the ductal cells. KEG virus caused a similarly high efficiency of infection. After blockage of basolateral base loaders, BDG infection significantly elevated -J(B-) 24 h after the infection, compared to the non-infected group. However, KEG infection did not modify -J(B-). After alkali loading the ducts, -J(B-) was significantly elevated in the BDG group compared to the control group 24 h after the infection. As we found with the inhibitor stop method, no change was observed in the group KEG compared to the non-infected group.
Incubation with the BDG or KEG strains of PRV results in an effective infection of ductal epithelial cells. The BDG strain of PRV, which is able to initiate a lytic viral cycle, stimulates HCO(3)(-) secretion in guinea pig pancreatic duct by about four- to fivefold, 24 h after the infection. However, the KEG strain of PRV, which can infect, but fails to replicate, has no effect on HCO(3)(-) secretion. We suggest that this response of pancreatic ducts to virulent PRV infection may represent a defense mechanism against invasive pathogens to avoid pancreatic injury.
World Journal of Gastroenterology 11/2005; 11(38):5997-6002. · 2.47 Impact Factor
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ABSTRACT: The sphincter of Oddi (SO) plays an important role in delivery of bile into the duodenum. To establish whether vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) were involved in phasic contractile activity of the rabbit SO stimulated by cholecystokinin-octapeptide (CCK-8).
Isolated SO muscle rings were cleaned of fat and mounted horizontally on two small L-shaped hooks one of which was connected to a force transducer for the measurement of isometric tension. The experiments were carried out in a thermostatically controlled (37+/-0.2 degrees) organ bath (5 mL) containing Krebs solution. The organ fluid was gassed with 95% O(2) and 50 mL/L CO(2) to keep the pH at 7.40+/-0.05. Contractile responses to CCK-8 (1 micromol/L) were evaluated in the presence and absence of N(G)-nitro-L-arginine (LNNA), an inhibitor of NO synthase (100 micromol/L), and (p-chloro-D-Phe(6)-Leu(17))-VIP (VIPa, 30 micromol/L), a VIP receptor antagonist.
CCK-8 stimulated the phasic activity of the SO. NO synthase inhibition increased the frequency and amplitude of contractions with a slight increase in developed tension. Pre-incubation with VIPa also attenuated this CCK-8 effect. The combined application of LNNA and VIPa abolished the phasic activity of the muscle rings with a marked increase in tension in response to CCK-8.
VIP and NO together contribute to an increase in phasic activity of SO.
World Journal of Gastroenterology 07/2005; 11(21):3264-6. · 2.47 Impact Factor
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ABSTRACT: 1. Vizsgálataink fontos eredménye egy új, jól standardizálható kísérletes akut pancreatitis modell kifejlesztése. Az arginin metabolitok vizsgálata során azt találtuk, hogy l-ornitinnel pancreas elhalással járó pancreatitis váltható ki patkányokban. A modell lehetőséget ad a kórfolyamatok tanulmányozása mellett a preventív hatású szerek kísérletes tesztelésére is. 2. Megállapítottuk, hogy a nekrózissal járó formákban észlelhető gyulladásos mediátorok szabályozásában az NF-?B transzkripiós faktor központi szerepet játszik. 3. Az NF-?B aktivációját szteroid-dependens mechanizmusok is regulálják. Glükokortikoid csökkenti, szteroid receptor antagonisa fokozza az aktivációt. 4. Igazoltuk, hogy a pancreatitis szövődményeinek kialakulásában a makrofág migráció gátló faktor (MIF), a késői szövődményekben a high mobilty group box protein 1 (HMGB1), és szolubilis receptorának (sRAGE) központi patogenetikai szerepe van. 5. Biliáris akut pancreatitis vizsgálata során kimutattuk, hogy epesavak (pl. chenodeoxykólsav) dózisfüggően csökkentik a pancreas duktális bikarbonát szekréciót, ami jelentősen befolyásolja a bilio-pancreaticus reflux elleni védelemet. 6. Fontos eredményünk a proteosoma inhibitorok protektív hatásának kimutatása kísérletes akut pancreatitisben. Bortezomid hatását vizsgálva azt találtuk, hogy a szer hősokk fehérje (HSP) indukcióra is képes. A bortezomid klinikai kipróbálása a humán akut pancreatitis kezelésében is előrelépést hozhat. | 1. We have developed a new and well-standardized pancreatitis model in rats. Administration of l-ornitine evoked a severe necrotizing pancreatitis. This model allows us to study the pathogenesis of acute pancreatitis and to test the protective effect of new drug candidate molecules. 2. Our studies revealed the pivotal role of the transcriptional factor NF-?B in the regulation of inflammatory processes in severe necrotizing pancreatitis. The activation of NF-kappaB is regulated by steroid dependent mechanisms. NF-?B activation is decreased in response to glucocoriticoids whereas steroid receptor antagonists increase the process. 4. We have demonstrated that the early complications of pancreatitis are mediated by macrophage migration inhibitory factor (MIF), whereas high mobilty group box protein 1 (HMGB1) and its soluble receptor (sRAGE) are responsible for the late complications of the disease. 5. In vitro studies revealed a dose-dependent inhibitory effect of different bile salts (chenodeoxycholic acid) on pancreatic ductal bicarbonate secretion. The inhibitory effect of CDCA result in a decreased protective capacity of pancreatic ducts in case of biliary reflux. 6. We have proved the protective effect of different proteosome inhibitors in experimental acute pancreatitis. Bortezomide was also demonstrated to induce heat shock proteins (HSPs). The clinical application of this candidate drug in acute pancreatitis may result new perspectives in the line of treatment options.
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ABSTRACT: Choleszterin gazdag diétával kiváltott hyperlipidemia nem befolyásolta az enyhe, ödémás pancreatitist, de súlyosbította a nekrotizáló pancreatitist. Hyperlipidemia csökkentette az endogén gyökfogók és a cNOS szintjét, iNOS és NF-kB aktivációt idézett elő és fokozta az ONOO- képződést a pancreasban. Ezen eltérések lehetnek felelősek a nekrotizáló pancreatitis súlyosbodásáért. Akut pancreatitis esetén az enterális táplálás az állatok súlyvesztését, a mortalitást, a pancreatitis súlyosságát és a pancreas bakteriális felülfertőződését mérsékelte, a pancreas regenerációját gyorsította. Ezen hatásokért a bélbe jutó táplálék trophicus hatása és a bélnyálkahártya integritásáért felelős nitrogén oxid anyagcserében bekövetkező kedvező változások tehetők felelőssé. A biopsziás mintavétel nem teljesen megbízható a sessilis nyálkahártya léziók azonosításában. Ezért egy adott léziónál, a méretétől és a típusától függően a teljes, endoszkópos eltávolításra kell törekedni, hogy biztos diagnózist lehessen felállítani, ill. így egyben végleges terápiát is lehet nyújtani. Szteroid terápia klinikai, morfológiai és funkcionális regressziót eredményez autoimmun pancreatitisben. Az MR képalkotás a morfológiai és a funkcionális változásokat egyaránt képes detektálni a hasnyálmirigyben. Ez növeli a vizsgálómódszer diagnosztikus hatékonyságát a krónikus pancreatitis korai felismerésében. | Hyperlipidemia induced with cholesterol-enriched diet did not worsen edematous, but aggravated necrotizing pancreatitis. Hyperlipidemia leads to decreases in endogenous scavenger and cNOS activities, results in iNOS and NF-?B activation and stimulates ONOO- generation in the pancreas, which may be responsible for the aggravation of acute necrotizing pancreatitis. Enteral feeding reduces the weight loss, mortality, the severity of acute pancreatitis, and the bacterial superinfection of pancreas, fasten the regeneration of pancreas in experimental acute pancreatitis. The trophic effects of nutriments in the gut, and the favorable modification in nitric oxide metabolism are responsible for these changes. Forceps biopsy is insufficiently reliable for the identification of gastric polyps. These lesions should be fully resected by endoscopic mucosal resection for a final diagnosis and (depending on the lesion size and type) possibly definitive treatment. Steroid therapy is clinically, morphologically, and functionally effective in patients with autoimmun pancreatitis. MRCP permits visualization of the ductal changes and furnishes functional information on the pancreas; this combination may enhance its diagnostic accuracy so that MRCP can become a valuable diagnostic means in early-stage chronic pancreatitis.
