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)

Calcium sensing receptor (CaSR) mutations implicated in familial hypocalciuric hypercalcemia, pancreatitis and idiopathic epilepsy syndrome map to an extended arginine-rich region in the proximal carboxyl terminus. Arginine-rich motifs mediate endoplasmic reticulum retention and/or retrieval of multisubunit proteins so we asked whether these mutations, R886P, R896H or R898Q, altered CaSR targeting to the plasma membrane. Targeting was enhanced by all three mutations, and Ca(2+)-stimulated ERK1/2 phosphorylation was increased for R896H and R898Q. To define the role of the extended arginine-rich region in CaSR trafficking, we independently determined the contributions of R890/R891 and/or R896/K897/R898 motifs by mutation to alanine. Disruption of the motif(s) significantly increased surface expression and function relative to wt CaSR. The arginine-rich region is flanked by phosphorylation sites at S892 (protein kinase C) and S899 (protein kinase A). The phosphorylation state of S899 regulated recognition of the arginine-rich region; S899D showed increased surface localization. CaSR assembles in the endoplasmic reticulum as a covalent disulfide-linked dimer and we determined whether retention requires the presence of arginine-rich regions in both subunits. A single arginine-rich region within the dimer was sufficient to confer intracellular retention comparable to wt CaSR. We have identified an extended arginine-rich region in the proximal carboxyl terminus of CaSR (residues R890 - R898) which fosters intracellular retention of CaSR and is regulated by phosphorylation. Mutation(s) identified in chronic pancreatitis and idiopathic epilepsy syndrome therefore increase plasma membrane targeting of CaSR, likely contributing to the altered Ca(2+) signaling characteristic of these diseases.
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PMID:Calcium sensing receptor mutations implicated in pancreatitis and idiopathic epilepsy syndrome disrupt an arginine-rich retention motif. 2079 21

Background and Aim. There are no accurate methods of differentiating acute biliary pancreatitis. Obstructions of biliary ducts, idiopathic pancreatitis may be related with biliary origin which needs identification for acute treatment. We searched for the predictivity of biochemical markers in early acute biliary pancreatitis. Patients and Methods. Serum levels of AST (Aspartate Transaminase),ALT (Alanine Transaminase), ALP (Alkaline Phosphatase), GGT (Gamma Glutamyl Transferase), total bilirubin, direct bilirubin, LDH (Lactate Dehydrogenase), amylase, lipase, CRP (C-Reactive Protein) and WBC (White Blood Cell) were measured in 157 patients with acute pancreatitis. Biliary and nonbiliary pancreatitis were differentiated by Magnetic Resonance Cholangiopancreatography (MRCP), Endoscopic Retrograde Cholangiopancreatography (ERCP), Intraoperative Cholangiopancreatography (IOC). Cut-off points of admission biochemical markers with sensitivity, specifity, positive predictive value and negative predictive value were determined after identification of significant variables. Receiver Operator Curves were plotted for each biochemical marker. Results. Serum Alkaline Phosphatase, total bilirubin, direct bilirubin, amylase and lipase levels were significantly higher in biliary pancreatitis with a positive predictive value of 80.8%, 83.9%, 81.6%, 78.8%, 79.7%. Conclusion. Increased Alkaline Phosphatase,total bilirubin, direct bilirubin, amylase and lipase levels may be used in prediction of biliary pancreatitis.
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PMID:The predictivity of serum biochemical markers in acute biliary pancreatitis. 2199 1

Acute pancreatitis is a frequent pathology with 11,000 to 13,000 new cases per year in France. A biliary origin (30 to 70% of the cases) should be suspected when alanine amino-transferases are elevated during the first 48 hours, and it is confirmed by the presence of gallstones at trans abdominal ultrasound. Abdominal computed-tomography scan is performed around the fifth day, and is repeated according to clinical and biological evolution. Management of acute biliary pancreatitis varies according to its severity, which should be assessed according to systemic inflammatory response syndrome and organ failures. For mild acute pancreatitis, cholecystectomy should be performed during in-hospital stay, before oral feeding. For moderately severe and severe acute pancreatitis, treatment is based on resuscitation, early enteral continuous feeding, and management of complications. Interval cholecystectomy is performed at a later stage. Endoscopic retrograde cholangiopancreatography with sphincterotomy should be performed in emergency when angiocholitis is associated, and in delayed emergency before oral feeding for persistent common bile duct stone. A common bile duct stone should be searched for during cholecystectomy and can be treated during the same surgical procedure if local conditions are adequate. Cholelithiasis is the most frequent cause of acute pancreatitis during pregnancy, and its diagnosis and the treatment have some particularities.
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PMID:Management of biliary acute pancreatitis. 3038 71

Intra-pancreatic activation of trypsin is an early event in pancreatitis. Trypsinogen can be activated to trypsin either through autoactivation (trypsin-mediated trypsinogen activation) or by the lysosomal protease cathepsin B (CTSB). Experimental separation of CTSB-mediated activation from autoactivation in mice is possible through knocking in mutations that render trypsinogen sensitive to CTSB but resistant to trypsin. Here we present biochemical studies on novel mouse cationic trypsinogen (isoform T7) mutants engineered for selective CTSB activation. First, we demonstrated that mutation K24G, which alters the activation site Lys in T7 trypsinogen, abolished autoactivation while activation by CTSB was stimulated 4-fold at pH 4.0. Interestingly, CTSB-mediated activation of the K24G mutant became more sensitive to inhibition by increasing pH. Next, Ala-scanning of the five Asp residues preceding the activation site Lys revealed that mutation D22A accelerated CTSB-mediated activation by 2-fold. Finally, combination of mutations D22A and K24G resulted in a trypsinogen mutant that exhibited 14-fold increased activation by CTSB and normal pH sensitivity. We conclude that we successfully engineered a mouse T7 trypsinogen mutant (D22A,K24G), which is robustly activated by CTSB but cannot undergo autoactivation. These studies set the stage for the generation of a preclinical mouse model of CTSB-dependent pancreatitis.
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PMID:Engineering mouse cationic trypsinogen for rapid and selective activation by cathepsin B. 3123 32

Intrapancreatic activation of digestive proteases, trypsin and chymotrypsin in particular, is a hallmark of pancreatitis. In experimental rodent models, protease activation is routinely measured from pancreatic homogenates using fluorogenic peptide substrates. Here we investigated the optimal conditions for the determination of intrapancreatic trypsin and chymotrypsin activation elicited by a single intraperitoneal injection of cerulein in C57BL/6N mice. We found that these protease assays were significantly improved by using lower amounts of pancreatic homogenate and exclusion of bovine serum albumin from the assay buffer. Furthermore, pancreatic homogenates had to be freshly prepared and assayed; as freezing and thawing stimulated protease activation. Finally, replacement of the widely used Boc-Gln-Ala-Arg-AMC trypsin substrate with Z-Gly-Pro-Arg-AMC reduced the background activity in saline-treated control mice and thereby increased the extent of cerulein-induced trypsin activation. Using the optimized protocol, we reproducibly measured 20-fold and 200-fold increases in the intrapancreatic trypsin and chymotrypsin activity, respectively, in mice given cerulein.
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PMID:Measuring digestive protease activation in the mouse pancreas. 3189 36


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