Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
PMID:Human mesotrypsin is a unique digestive protease specialized for the degradation of trypsin inhibitors. 1450 9

Excessive ethanol consumption is a common risk factor for acute and chronic pancreatitis. Ethanol could lead to the onset of pancreatitis in a number of ways; the most recently discovered is its effect on intrapancreatic digestive enzyme activation, by either sensitizing acinar cells to pathologic stimuli or stimulating the release of a secretagogue (cholecystokinin) from duodenal I cells. Recent advances in cell biologic and molecular techniques have permitted us to address the intracellular events involved in digestive enzyme activation in a manner that was previously considered impossible. Investigations that used these novel techniques found that (a) trypsin is, in contrast to its role in the small intestine, not necessarily involved in the premature intracellular activation of other digestive proteases such as proelastase; (b) trypsinogen does not autoactivate intracellularly but is instead largely activated by the lysosomal hydrolase cathepsin B; and (c) the role of trypsin in the intrapancreatic protease cascade is most likely one that involves the degradation, rather than the activation, of active digestive proteases including trypsin itself. These studies, as well as investigations that have addressed the role of mutant trypsin in the disease onset of hereditary pancreatitis, suggest that trypsin may not be critical for triggering pancreatitis but might have a protective role against the action of some of the other digestive proteases. While the specific role of different digestive enzymes in initiating pancreatitis is still a matter of debate and the topic of ongoing investigations, experimental evidence suggests that ethanol can directly interfere with the processes involved in digestive zymogen activation.
 ...
PMID:Pathophysiology of alcohol-induced pancreatitis. 1457 89

The lysosomal protease cathepsin B has been implicated in a variety of pathologies including pancreatitis, tumor angiogenesis, and neuronal diseases. We used a tube formation assay to investigate the role of cathepsin B in angiogenesis. When cultured between two layers of collagen I, primary endothelial cells formed tubes in response to exogenously added VEGF. Overexpressing cathepsin B reduced the VEGF-dependent tube response, whereas pharmacologically or molecularly suppressing cathepsin B eliminated the dependence on exogenous VEGF. However, tube formation still required VEGF receptor activity, which suggested that endothelial cells generated VEGF. Indeed, VEGF mRNA and protein was detectable in cells treated with cathepsin B inhibitor, which correlated with a rise in the level of HIF-1alpha. In addition to boosting the level of proangiogenic factors, blocking cathepsin B activity reduced the amount of the antiangiogenic protein endostatin. Thus endothelial cells have the intrinsic capacity to generate pro- and antiangiogenic agents. These observations complement and expand our appreciation of how endothelial cell-derived proteases regulate angiogenesis.
 ...
PMID:Cathepsin B regulates the intrinsic angiogenic threshold of endothelial cells. 1590 32

A wide range of mutations and polymorphisms in genes that relate to pancreatic function seem to be involved in the development of pancreatitis. Some of these genetic alterations lead to disease phenotypes with unequivocal mendelian inheritance patterns, whereas others seem to act as modifier genes in conjunction with environ-mental or, as yet unidentified, genetic cofactors. This article reviews germline changes in the genes for trypsin, pancreatic secretory trypsin inhibitor, the cystic fibrosis conductance regulator, lipid metabolism proteins, inflammatory mediators for cytokines, and cathepsin B.
 ...
PMID:Germline mutations and gene polymorphism associated with human pancreatitis. 1663 93

Efforts to unravel the intracellular processes that occur in acute pancreatitis continue. In cerulein pancreatitis, new evidence supports the idea that a very early event is premature trypsinogen activation triggered by lysosomal cathepsin B. Clinicians persist in trying to identify more sensitive and specific prognostic signs of the severity of attacks of pancreatitis; one study suggests that computer-based neural networks may be an alternative to biochemical markers and clinical scoring systems. The systemic severity of episodes of pancreatitis seems to be related to a multitude of proinflammatory cytokines and chemokines acting at sites distant from the pancreas. Selective blockade of some of these peptides (eg, endothelin-1 and platelet-activating factor) has decreased mortality and distant organ damage in animal models and may deserve clinical evaluation. Gene therapy may be more efficient than pharmacologic therapy in increasing anti-inflammatory cytokine (interleukin-10) levels. Clinical studies have further underlined the usefulness of prophylactic antibiotics in severe acute pancreatitis. Radiologic and endoscopic techniques may be alternatives to surgery for certain complications of pancreatitis (eg, infected necrosis and pseudocysts) in particular subsets of patients.
 ...
PMID:Acute pancreatitis. 1702 79

Alcoholic liver disease (ALD) and alcoholic pancreatitis (AP) are major diseases causing high mortality and morbidity among chronic alcohol abusers. Neutral lipid accumulation (steatosis) is an early stage of ALD or AP and progresses to inflammation and other advanced stages of diseases in a subset of chronic alcohol abusers. However, the mechanisms of alcoholic steatosis leading to ALD and AP are not well understood. Chronic alcohol abuse impairs hepatic alcohol dehydrogenase (ADH, a major enzyme involved in ethanol oxidative metabolism) and facilitates nonoxidative metabolism of ethanol to fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol). These esters are implicated in the pathogenesis of various alcoholic diseases and shown to cause hepatocellular and pancreatitis-like injury. Ethanol exposure is known to increase synthesis of FAEEs by several-fold in the livers and pancreata of rats pretreated with hepatic ADH inhibitor. Therefore, studies were undertaken to evaluate hepatocellular and pancreatic injury in hepatic ADH-deficient (ADH(-)) deer mice versus ADH-normal (ADH(+)) deer mice fed ethanol (4% wt/vol) via Lieber-DeCarli liquid diet for 60 days. A significant mortality was found in ethanol-fed ADH(-) deer mice (11 out of 18) versus ADH(+) deer mice (1 out of 16); most of the deaths occurred during the first 2 weeks of ethanol exposure. The surviving animals, sacrificed at the end of 60th day, showed distinct changes in hepatic and pancreatic histology and several-fold increases in nonoxidative metabolism of ethanol in ethanol-fed ADH(-) versus ADH(+) deer mice. Extensive vacuolization with displacement or absence of nucleus in some hepatocytes, and significant increase in hepatic neutral lipids were found in ethanol-fed ADH(-) versus ADH(+) deer mice. Ultrastructural changes showed perinuclear space, edema, presence of apoptotic bodies and disintegration, and/or dilatation of endoplasmic reticulum (ER) in the pancreata of ethanol-fed ADH(-) deer mice. FAEE levels were significantly higher in ADH(-) versus ADH(+) deer mice, approximately four-fold increases in the livers and seven-fold increases in the pancreata. Ethyl esters of oleic, linoleic, and arachidonic acids were the major FAEEs detected in ethanol-fed groups. The role of FAEEs in pancreatic lysosomal fragility is reflected by higher activity of cathepsin B (five-fold) in ethanol-fed ADH(-) versus ADH(+) deer mice. Although the present studies clearly indicate a metabolic basis of ethanol-induced hepatic and pancreatic injury, detailed dose- and time-dependent toxicity studies in this ADH(-) deer mouse model could reveal further a better understanding of mechanism(s) of ethanol-induced hepatic and pancreatic injuries.
 ...
PMID:Metabolic basis of ethanol-induced hepatic and pancreatic injury in hepatic alcohol dehydrogenase deficient deer mice. 1712 37

Proteases play a regulatory role in a variety of pathologies including cancer, pancreatitis, thromboembolic disorders, viral infections and many others. One of the possible strategies how to combat with these pathologies seems to be the use of low molecular inhibitors. Natural products were evaluated in the in vitro antiprotease assay on serine proteases (trypsin, thrombin and urokinase) and on the cysteine protease cathepsin B. We found interesting results for beta-ursolic acid isolated from Salvia officinalis, which significantly inhibited all tested proteases in vitro in the micromolar range. beta-Ursolic acid showed the strongest inhibition activity to urokinase (IC50 = 12 microM) and cathepsin B (IC50 = 10 microM) as proteases included in tumour invasion and metastasis indicated possible anticancer effectivity. Therefore, we tested the ability of beta-ursolic acid at doses of 50, 75 and 100 mg/kg given i.p. to inhibit lung colonization of beta16 mouse melanoma cells in vivo. We found, that beta-ursolic acid significantly decreased the number of B16 colonies in the lungs of mice at the dose 50 mg/kg (p < 0.05).
 ...
PMID:Antiprotease and antimetastatic activity of ursolic acid isolated from Salvia officinalis. 1729 86

We have hypothesized that the colocalization of digestive zymogens with lysosomal hydrolases, which occurs during the early stages of every experimental pancreatitis model, facilitates activation of those zymogens by lysosomal hydrolases such as cathepsin B and that this activation triggers acute pancreatitis by leading to acinar cell injury. Some, however, have argued that the colocalization phenomenon may be the result, rather than the cause, of zymogen activation during pancreatitis. To resolve this controversy and explore the causal relationships between zymogen activation and other early pancreatitis events, we induced pancreatitis in mice by repeated supramaximal secretagogue stimulation with caerulein. Some animals were pretreated with the cathepsin B inhibitor CA-074 me to inhibit cathepsin B, prevent intrapancreatic activation of digestive zymogens, and reduce the severity of pancreatitis. We show that inhibition of cathepsin B by pretreatment with CA-074 me prevents intrapancreatic zymogen activation and reduces organellar fragility, but it does not alter the caerulein-induced colocalization phenomenon or subcellular F-actin redistribution or prevent caerulein-induced activation of NF-kappaB, ERK1/2, and JNK or upregulated expression of cytochemokines. We conclude 1) that the colocalization phenomenon, F-actin redistribution, activation of proinflammatory transcription factors, and upregulated expression of cytochemokines are not the results of zymogen activation, and 2) that these early events in pancreatitis are not dependent on cathepsin B activity. In contrast, zymogen activation and increased subcellular organellar fragility during caerulein-induced pancreatitis are dependent on cathepsin B activity.
 ...
PMID:Cause-effect relationships between zymogen activation and other early events in secretagogue-induced acute pancreatitis. 1733 71

Acute pancreatitis is an autodigestive disease, in which the pancreatic tissue is damaged by the digestive enzymes produced by the acinar cells. Among the tissues in the mammalian body, pancreas has the highest concentration of the natural polyamine, spermidine. We have found that pancreas is very sensitive to acute decreases in the concentrations of the higher polyamines, spermidine and spermine. Activation of polyamine catabolism in transgenic rats overexpressing SSAT (spermidine/spermine-N(1)-acetyltransferase) in the pancreas leads to rapid depletion of these polyamines and to acute necrotizing pancreatitis. Replacement of the natural polyamines with methylated polyamine analogues before the induction of acute pancreatitis prevents the development of the disease. As premature trypsinogen activation is a common, early event leading to tissue injury in acute pancreatitis in human and in experimental animal models, we studied its role in polyamine catabolism-induced pancreatitis. Cathepsin B, a lysosomal hydrolase mediating trypsinogen activation, was activated just 2 h after induction of SSAT. Pre-treatment of the rats with bismethylspermine prevented pancreatic cathepsin B activation. Analysis of tissue ultrastructure by transmission electron microscopy revealed early dilatation of rough endoplasmic reticulum, probable disturbance of zymogen packaging, appearance of autophagosomes and later disruption of intracellular membranes and organelles. Based on these results, we suggest that rapid eradication of polyamines from cellular structures leads to premature zymogen activation and autodigestion of acinar cells.
 ...
PMID:Mechanisms of polyamine catabolism-induced acute pancreatitis. 1737 Dec 71

Alcohol exposure is known to sensitize acinar cells to various insults but the pathophysiological mechanisms of alcoholic pancreatitis remain unknown. Alcohol abuse has been shown to mediate an anti-inflammatory response and periods of immune suppression seem to be associated with organ injury and mortality. The purpose of this study was to determine the mechanisms by which alcohol exerts transcriptional activities in the rat pancreas and how alcohol alters the inflammatory response. Using the Lieber-DeCarli alcohol/control diet, rats that were fed with alcohol over 14 weeks demonstrated a decrease of inflammatory cells in pancreatic tissue compared to controls. The anti-inflammatory effects of alcohol were confirmed by decreased expression of pro-inflammatory cytokines including TNFalpha, IL-1beta, IL-18, TGFbeta, and MCP-1. In addition, alcohol significantly increased the activity of PPARgamma, which is a known anti-inflammatory transcription factor, while pro-inflammatory factors including AP-2 and EGR-1 were significantly suppressed. NFkappaB binding showed a tendency towards a reduction. Electron microscopy studies revealed enlarged and injured mitochondria and lysosomes, accompanied by peri-cellular fibrosis. Furthermore, alcohol exposure increased the activities of trypsin and cathepsin B, both known to be critical in initiating acinar cell injury and pancreatitis. Despite the known alcohol-mediated acinar cell and mitochondrial injury, the mitochondrial-mediated apoptotic pathway was attenuated. These data demonstrate that the pancreas exposed to alcohol maintains an anti-inflammatory state by activating PPARgamma. Intracellular mitochondrial and lysosomal damage after chronic alcohol exposure induces premature activation of digestive enzymes and establishment of peri-cellular fibrosis in the absence of inflammation.
 ...
PMID:Immune-compromised state in the rat pancreas after chronic alcohol exposure: the role of peroxisome proliferator-activated receptor gamma. 1793 47


<< Previous 1 2 3 4 5 6 7 8 9 Next >>