Effects of several regulatory peptides on the functional activity of the pancreas in acute experimental pancreatitis

The influence of regulatory peptides (somatostatin, calcitonin, and dalargin) on xanthine oxidase activity and lipid peroxidation level in pancreatic tissues as well as on the release of pancreatic enzymes (alpha-amylase, trypsin, lipase, and transamidinase) into blood was studied in 205 rats with experimental acute pancreatitis. Somatostatin and dalargin were shown to have obvious antioxidant effect seen by reduced xanthine oxidase activity and MDA level. All studied peptides stimulate reduced release of pancreatic enzymes. Particularly, reduction of dalargin and somatostatin is caused by inhibition of their synthesis as well as by pancreas protective effect of the peptides. Release of enzymes reduced by calcitonin is probably associated only with inhibition of secretory activity of the pancreas.     

Effect of somatostatin on bile-induced acute hemorrhagic pancreatitis in the dog.

In 21 female Beagle dogs an experimental pancreatitis was induced by injection of bile into the pancreatic duct system. Beside controls, dogs received 62.5 micrograms/h cyclic somatostatin (SRIF) a continuous i.v. infusion starting with a bolus of 250 micrograms 15 minutes before or 2 hours after bile injection. Following blood parameters were determined: lipase, amylase, blood count, minerals, glucose, insulin, gastrin, secretin and CCK. Two controls died within 24 hours, the others were sacrificed after 48 hours. All pancreata were examined morephologically. The controls developed all clinical signs of acute hemorrhagic pancreatitis, whereas all SRIF-treated dogs were in much better general condition. Lipase and amylase increased in all groups. In the controls insulin, gastrin and secretin remained unchanged and CCK rose slightly. SRIF-treatment diminished insulin, CCK and the test meal-induced increase of secretin. At autopsy the pancreata of the controls were nearly entirely apoplectic. The SRIF-treated dogs showed less damage of the pancreas and no severe hemorrhagic necrosis was noted. The beneficial effect of SRIF cannot only be due to an interaction with intestinal hormones. An additional direct protective effect on the exocrine parenchyma is proposed to exist.     

Effect of sodium thiosulfate on the pancreas in experimental pancreatitis]

Histological and histochemical study of the pancreas of albino rats and experimental pancreatitis showed the use of sodium thiosulfate to considerably inhibit the progress of necrotic changes and circulatory disturbance. The preparation prevented recidivation of pancreatitis and inhibited sclerotic changes in the gland. Sodium thiosulfate stimulated the regenerative process including regenerative hypertrophy and expressed epimorphosis.     

Effect of sodium thiosulfate on viable areas of the pancreas in experimental pancreatitis

Experimental pancreatitis in white rats is marked by stromal edema, dystrophic changes of acinar cells, with intracellular edema in an intact part of the pancreas. Subsequently the acinar cells undergo intracellular regeneration and hypertrophy, which is accompanied by intensive incorporation of 14C-leucin into glandular proteins. Sodium thiosulfate prevents the development of stromal edema and intracellular edema of the acinar cells and retards the development of acinar cell hypertrophy. The drug produces an inhibitory action on 14C-leucin incorporation into pancreatic proteins.     

Expression profiling in pancreas during the acute phase of pancreatitis using cDNA microarrays

Most attacks of acute pancreatitis are self-limiting, suggesting that the pancreatic cells adapt their phenotype to prevent progression of the disease. Such phenotypic change must involve a coordinated modification in the expression of numerous genes. To identify differentially expressed genes, high-density mouse cDNA microarrays were hybridized with cDNA probes from both healthy pancreas and pancreas affected by acute pancreatitis. From the 7981 mouse genes analyzed, 239 showed significant changes in their expression during the acute phase of pancreatitis. Among them, 107 genes were up-regulated whereas 132 were down-regulated. They include genes whose function was not previously related to pancreatitis, suggesting that they are involved in some way into the acute pancreatic response. Finally, 40% of differentially expressed genes corresponded to ESTs. Demonstration that a large quantity of unexpected or yet uncharacterized genes showed altered expression during acute pancreatitis underscores the interest of a genome-based investigation. Some of these genes are certainly involved in the cellular defense against pancreatitis and, as such, deserve being studied further.     

Crystal structure of the C. perfringens alpha-toxin with the active site closed by a flexible loop region

Clostridium perfringens biotype A strains are the causative agents of gas-gangrene in man and are also implicated as etiological agents in sudden death syndrome in young domestic livestock. The main virulence factor produced by these strains is a zinc-dependent, phosphatidylcholine-preferring phospholipase C (alpha-toxin). The crystal structure of alpha-toxin, at pH 7.5, with the active site open and therefore accessible to substrate has previously been reported, as has calcium-binding to the C-terminal domain of the enzyme at pH 4.7. Here we focus on conformation changes in the N-terminal domain of alpha-toxin in crystals grown at acidic pH. These changes result in both the obscuring of the toxin active site and the loss of one of three zinc ions from it. Additionally, this "closed" form contains a small alpha helix, not present in the open structure, which hydrogen bonds to both the N and C-terminal domains. In conjunction with the previously reported findings that alpha-toxin can exist in active and inactive forms and that Thr74Ile and Phe69Cys substitutions markedly reduced the haemolytic activity of the enzyme, our work suggests that these loop conformations play a critical role in the activity of the toxin.     

Effect of synthetic analogs of L-enkephalin on viable areas of the pancreas in experimental pancreatitis

Synthetic analogues of L-enkephalin--tageflar and dalargin were studied for the treatment of experimentally-induced pancreatitis of rats. It was concluded that morphometric features of an intact part of the pancreas were not significantly changed with the use of tageflar. The intensity of 14C-leucine inclusion in the proteins of an intact part of the pancreas was strongly suppressed and the cytoplasm of exocrine pancreocytes was overloaded with zymogen granules. With the use of dalargin, a moderate hypertrophy of exocrine pancreocytes and intensification of 14C-leucine inclusion developed gradually. The number and disposition of zymogen granules were not significantly changed, as compared to acute pancreatitis. Both drugs disturbed the process of acinar reconstruction into tubular complexes in the marginal areas.