Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mesotrypsin is an enigmatic minor human trypsin isoform, which has been recognized for its peculiar resistance to natural trypsin inhibitors such as soybean trypsin inhibitor (SBTI) or human pancreatic secretory trypsin inhibitor (SPINK1). In search of a biological function, two conflicting theories proposed that due to its inhibitor-resistant activity mesotrypsin could prematurely activate or degrade pancreatic zymogens and thus play a pathogenic or protective role in human pancreatitis. In the present study we ruled out both theories by demonstrating that mesotrypsin was grossly defective not only in inhibitor binding, but also in the activation or degradation of pancreatic zymogens. We found that the restricted ability of mesotrypsin to bind inhibitors or to hydrolyze protein substrates was solely due to a single evolutionary mutation, which changed the serine-protease signature glycine 198 residue to arginine. Remarkably, the same mutation endowed mesotrypsin with a novel and unique function: mesotrypsin rapidly hydrolyzed the reactive-site peptide bond of the Kunitz-type trypsin inhibitor SBTI, and irreversibly degraded the Kazal-type temporary inhibitor SPINK1. The observations suggest that the biological function of human mesotrypsin is digestive degradation of trypsin inhibitors. This mechanism can facilitate the digestion of foods rich in natural trypsin inhibitors. Furthermore, the findings raise the possibility that inappropriate activation of mesotrypsinogen in the pancreas might lower protective SPINK1 levels and contribute to the development of human pancreatitis. In this regard, it is noteworthy that the well known pathological trypsinogen activator cathepsin B exhibited a preference for the activation of mesotrypsinogen of all three human trypsinogen isoforms, suggesting a biochemical mechanism for mesotrypsinogen activation in pancreatic acinar cells.
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PMID:Human mesotrypsin is a unique digestive protease specialized for the degradation of trypsin inhibitors. 1450 9

Although pain is a cardinal feature of pancreatitis, its pathogenesis is poorly understood and treatment remains difficult. Nociceptive sensitization in several somatic pain models has been associated with activation of protein kinases including trkA, protein kinase C, and protein kinase A. We therefore tested the hypothesis that systemic treatment with a kinase inhibitor, k252a, known to inhibit all of these kinases would alleviate pain in an animal model of pancreatitis. Von Frey filament testing of somatic referral regions was evaluated as a method to measure referred pain in a rat model of acute necrotizing pancreatitis induced by L-arginine. Rats with pancreatitis showed increased sensitivity to abdominal stimulation with Von Frey filament. This referred mechanical sensitivity was associated with an 8-fold increase in levels of phosphorylated trkA in the pancreas and with significant up-regulation of both calcitonin gene-related peptide and preprotachykinin mRNA expression in thoracic dorsal root ganglia and with increased calcitonin gene-related peptide and substance P immunoreactivity in spinal cord segment T10. Treatment with the kinase inhibitor k252a suppressed the phosphorylation of trkA in the pancreas as well as reversed both the behavioral changes and the increase in neuropeptide expression associated with pancreatitis.
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PMID:Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor k252a. 1462 90

Despite medical treatment, the lethality of severe acute pancreatitis is still high (20-30%). Therefore, it is very important to find good animal models to characterise the events of this severe disease. In 1984, Mizunuma et al. developed a new type of experimental necrotizing pancreatitis by intraperitoneal administration of a high dose of L-arginine in rats. This non-invasive model is highly reproducible and produces selective, dose-dependent acinar cell necrosis. Not only is this a good model to study the pathomechanisms of acute necrotizing pancreatitis, but it is also excellent to observe and influence the time course changes of the disease. By writing this review we illuminate some new aspects of cell physiology and pathology of acute necrotizing pancreatitis. Unfortunately, the reviews about acute experimental pancreatitis usually did not discuss this model. Therefore, the aim of this manuscript was to summarise the observations and address some challenges for the future in L-arginine-induced pancreatitis.
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PMID:L-arginine-induced experimental pancreatitis. 1523 23

Arginine has been used by millions of athletes over the past 20 years to enhance production of human growth hormone. The effects of arginine supplementation include increased fat burning and muscle building, enhanced immunity, and improvement in erectile function in men. Excessive doses of basic amino acids such as ethionine, methionine and lysine are known to damage the rat pancreas. Recent studies have demonstrated that excessive doses of arginine induce necrotizing pancreatitis in rats. In this article, we report a 16-year-old male patient hospitalized in our clinic because of severe pain in upper abdomen, nausea and vomiting who was suspected to have arginine-induced acute pancreatitis.
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PMID:Acute pancreatitis possibly due to arginine use: a case report. 1526 24

For the first time, a direct sensitive method of *NO(2) detection and measurement in biological material has been established. It is based on the interaction of this radical with the coordination compound of Cr(III) with aminodeoxysugar as biosensor. Our new method makes it possible to precisely assess *NO(2) level in experimental acute necrotizing pancreatitis induced by L-arginine, where oxidative and nitrosative stresses are supposed to play a key role in the pathomechanism of the disease. As much as 20 nmol of *NO(2)/mg protein was detected which correlated with severe deterioration of pancreatic acinar cell ultrastructure. Protective effect of superoxide radical scavenger 4-OH-TEMPO expressed as *NO(2) level decrease confirmed by preserved acinar cell ultrastructure and decreased pancreatic amylase release to blood serum is demonstrated. This study reveals a possible pathomechanism of L-arginine induced acute pancreatitis.
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PMID:Pivotal participation of nitrogen dioxide in L-arginine induced acute necrotizing pancreatitis: protective role of superoxide scavenger 4-OH-TEMPO. 1558 79

Microcirculatory disturbances are important early pathophysiological events in various organs during acute pancreatitis (AP). The aim of the study was to investigate an influence of L-arginine (nitric oxide substrate) and N(G)-nitro-L-arginine (L-NNA, nitric oxide synthase inhibitor) on organ microcirculation in experimental acute pancreatitis induced by four consecutive intraperitoneal cerulein injections (15 microg/kg/h). The microcirculation of pancreas, liver, kidney, stomach, colon and skeletal muscle was measured by laser Doppler flowmeter. Serum interleukin 6 and hematocrit levels were analyzed. AP resulted in a significant drop of microperfusion in all examined organ. L-arginine administration (2 x 100 mg/kg) improved the microcirculation in the pancreas, liver, kidney, colon and skeletal muscle, and lowered hematocrit levels. L-NNA treatment (2 x 25 mg/kg) caused aggravation of edematous AP to the necrotizing situation, and increased IL-6 and hematocrit levels. A further reduction of blood perfusion was noted in the stomach only. It is concluded that L-arginine administration has a positive influence on organ microcirculatory disturbances accompanying experimental cerulein-induced AP. NO inhibition aggravates the course of pancreatitis.
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PMID:Organ microcirculatory disturbances in experimental acute pancreatitis. A role of nitric oxide. 1558 45

Hereditary pancreatitis is a rare autosomal dominant inherited disease with 80% penetration rate. The disease is characterized by recurrent episodes of pancreatitis often beginning in childhood, positive family history with at least two other affected members and no known precipitating factors. Most forms of hereditary pancreatitis are caused by one of two commoner mutations, R122H in exon 3 and N29I in exon 2 of the cationic trypsinogen (CT) (PRSS1) gene, located on chromosome 7. These genetic defects are speculated to cause excessive trypsin activity or to prevent inactivation of prematurely activated trypsin, resulting in pancreatitis. We performed mutation analysis of a Korean family with two members having clinically suspicious hereditary pancreatitis. We analyzed the CT gene in DNA samples extracted from peripheral blood of five family members. First of all, polymerase chain reaction and restriction enzyme digestion were performed in exon 3 of the CT gene. And then DNA products were purified and sequenced. We found out that three members of the family, the mother and two daughters, had a R122H mutation of the CT gene. We report the first family of hereditary pancreatitis associated with the CT gene mutation, an arginine to histidine amino acid substitution at residue 122, in Korea.
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PMID:[A case of R122H mutation of cationic trypsinogen gene in a pediatric patient with hereditary pancreatitis complicated by pseudocyst and hemosuccus pancreaticus]. 1572 20

Coxsackievirus B3 (CVB3) is a common human pathogen that is endemic throughout the world. There is currently no vaccine available, although the virus is known to be highly lethal to newborns and has been associated with heart disease and pancreatitis in older children and adults. Previously, we showed that the virulence of CVB3 is reduced by a lysine-to-arginine substitution in the capsid protein VP2 (K2168R) or a glutamic acid-to-glycine substitution in VP3 (E3060G). In this report, we show that the double mutant virus CVB3(KR/EG) displays additional attenuation, particularly for the pancreas, in A/J mice. In addition, two other attenuating mutations have been identified in the capsid protein VP1. When either the aspartic acid residue D1155 was replaced with glutamic acid or the proline residue P1126 was replaced with methionine, the resulting mutant also possessed an attenuated phenotype. Moreover, when either of these mutations was incorporated into CVB3(KR/EG), the resulting triple mutant viruses, CVB3(KR/EG/DE) and CVB3(KR/EG/PM), were completely noncardiovirulent and caused only small foci of damage to the pancreas, even at a high dose. Both triple mutants were found to be immunogenic, and a single injection of young A/J mice with either was found to protect them from a subsequent lethal challenge with wild-type CVB3. These findings indicate that the triple mutants could be exploited for the development of a live attenuated vaccine against CVB3.
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PMID:A genetically engineered attenuated coxsackievirus B3 strain protects mice against lethal infection. 1599 22

Effects of dexamethasone and N(G)-nitro-L-arginine methyl ester (L-NAME), the nitric oxide (NO) synthase inhibitor, on caerulein-induced acute pancreatitis were examined in rats. Acute pancreatitis was induced by caerulein (20 mug/kg, s.c.) given repeatedly 2 or 4 times every hour, and serum amylase levels, pancreas weight and myeloperoxidase (MPO) activity were measured 6 h after the first injection of caerulein. Dexamethasone (3 mg/kg) and L-NAME (30 mg/kg) were administered p.o. 30 min before the first injection of caerulein. Caerulein caused moderate or severe pancreatitis, depending on the times of injections, resulting in different degrees of increase in serum amylase levels and pancreas weight, and the marked elevation of MPO activity was observed only after injections of caerulein given 4 times per hour. Both dexamethasone and L-NAME suppressed the severity of pancreatits, yet the effect of L-NAME as compared with dexamethasone was more potent against mild pancreatitis but less potent against severe pancreatitis. These results suggest that caerulein-induced acute pancreatitis shows different responsiveness to L-NAME and dexamethasone, depending on the severity; the former is more effective against pancreatitis with less inflammation, while the latter is more effective against pancreatitis with severe inflammation. It is assumed that endogenous NO may be involved in oedema formation as the early event in the development of acute pancreatitis.
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PMID:Different effects of dexamethasone and the nitric oxide synthase inhibitor L-NAME on caerulein-induced rat acute pancreatitis, depending on the severity. 1625 48

The first family of hereditary pancreatitis was described in 1952. The mode of inheritance is autosomal dominant trait with an 80% of penetrance rate. Although hereditary pancreatitis is rare, this disorder has provided valuable insights in understanding the pathophysiology of pancreatitis and pancreatic cancer. The causative gene of hereditary pancreatitis was identified in 1996 through mutational analysis of genes within chromosome 7q35. Most forms of hereditary pancreatitis are caused by one of two common mutations, R122H in the third exon or N29I in the second exon of the cationic trypsinogen gene (protease serine 1, PRSS1). R122H mutation is the most common PRSS1 mutation. Additional mutations of the cationic trypsinogen gene have been described. In Korea, first family of hereditary pancreatitis with cationic trypsinogen gene mutation revealed an arginine to histidine amino acid substitution at the residue 122. Patients with hereditary pancreatitis present with symptoms at an early age and have significant risk for the development of chronic pancreatitis and pancreatic cancer. The risk of pancreatic cancer is estimated to be 53-fold higher after the age of 50 years than the general population. The risk of pancreatic cancer is not related to the type of mutation. Since hereditary pancreatitis is a strong risk factor for pancreatic cancer, it is important to establish a diagnostic criteria for diagnosis and surveillance. However, there are potential benefits, risks and limitations in genetic testing for hereditary pancreatitis. It is difficult to provide the proper treatment, but recent developments in therapeutic approaches may be helpful in caring hereditary pancreatitis. This article includes the current status, pathogenesis, clinical features, and management of hereditary pancreatitis including the aspects of pancreatic cancer.
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PMID:[Hereditary pancreatitis]. 1630 49


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