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Gastroenterology May 2019Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of... (Review)
Review
Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.
Topics: Animals; Apoptosis; Enzyme Activation; Genetic Predisposition to Disease; Humans; Inflammation Mediators; Mutation; Necrosis; Pancreas; Pancreatitis; Peptide Hydrolases; Phenotype; Prognosis; Protein Folding; Risk Factors; Signal Transduction
PubMed: 30660731
DOI: 10.1053/j.gastro.2018.11.081 -
American Journal of Veterinary Research Jun 2022Lipases are water-soluble enzymes that hydrolyze water-insoluble lipid molecules, such as triglycerides, phospholipids, and galactolipids. They are ubiquitous in nature... (Review)
Review
Lipases are water-soluble enzymes that hydrolyze water-insoluble lipid molecules, such as triglycerides, phospholipids, and galactolipids. They are ubiquitous in nature and are present in humans, animals, insects, plants, fungi, and microorganisms. While we commonly consider pancreatic lipase, this review provides an overview of several lipases that are important for the digestion and metabolism of lipids in veterinary species. All of these enzymes have specific functions but share a common α/β-hydrolase fold and a catalytic triad where substrate hydrolysis occurs. The pancreatic lipase gene family is one of the best characterized lipase gene families and consists of 7 mammalian subfamilies: pancreatic lipase, pancreatic lipase related proteins 1 and 2, hepatic lipase, lipoprotein lipase, endothelial lipase, and phosphatidylserine phospholipase A1. Other mammalian lipases that play integral roles in lipid digestion include carboxyl ester lipase and gastric lipase. Although most enzymes have preferred substrate specificity, much overlap occurs across the plethora of lipases because of the similarities in their structures. This has major implications for the development and clinical utilization of diagnostic assays. These implications are further explored in our companion Currents in One Health article by Lim et al in the August 2022 issue of the Journal of American Veterinary Medical Association, which focuses on pancreatic lipase assays for the diagnosis of pancreatitis.
Topics: Animals; Humans; Kinetics; Lipase; Pancreas; Triglycerides; Water
PubMed: 35895796
DOI: 10.2460/ajvr.22.03.0048 -
Physiological Reviews Jan 2002The traditional understanding is that an entirely new complement of digestive enzymes is secreted by the pancreas into the small intestines with each meal. This is... (Review)
Review
The traditional understanding is that an entirely new complement of digestive enzymes is secreted by the pancreas into the small intestines with each meal. This is thought to be necessary because, like food itself, these enzymes are degraded during digestion. In this review we discuss experiments that bring this point of view into question. They suggest that digestive enzymes can be absorbed into blood, reaccumulated by the pancreas, and reutilized, instead of being reduced to their constituent amino acids in the intestines. This is called an enteropancreatic circulation of digestive enzymes.
Topics: Animals; Biological Transport; Digestion; Enzymes; Humans; Intestinal Mucosa; Pancreas
PubMed: 11773607
DOI: 10.1152/physrev.00022.2001 -
Diabetes Care Sep 2008To further define clinical features associated with the syndrome of diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl-ester lipase (CEL) gene...
OBJECTIVE
To further define clinical features associated with the syndrome of diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl-ester lipase (CEL) gene and to assess the effects of pancreatic enzyme substitution therapy.
RESEARCH DESIGN AND METHODS
Nine patients with CEL gene mutation, exocrine deficiency, and diabetes were treated and followed for 30 months.
RESULTS
Treatment improved symptoms in seven of nine patients. Exocrine and endocrine function assessed by fecal elastase and A1C were not affected, although fecal lipid excretion was reduced. Vitamin E was low in all patients but increased with treatment (P < 0.001 at 30 months) and improved in five subjects. A predominantly demyelinating neuropathy was seen in a majority of patients, and carpal tunnel syndrome was common.
CONCLUSIONS
Pancreatic enzyme substitution alleviated symptoms and malabsorption and normalized vitamin E levels. Glycemic control was not significantly affected. The CEL syndrome seems associated with a demyelinating neuropathology.
Topics: Demyelinating Diseases; Enzyme Therapy; Feces; Glycated Hemoglobin; Humans; Islets of Langerhans; Lipase; Pancreas; Pancreatic Diseases; Pancreatic Elastase; Vitamin E
PubMed: 18544793
DOI: 10.2337/dc07-2217 -
World Journal of Gastroenterology Nov 2014A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic... (Review)
Review
A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic damage and is a major determinant of clinical severity. Thus, research has recently focused on molecules that can regulate the inflammatory processes, such as phosphoinositide 3-kinases (PI3Ks), a family of lipid and protein kinases involved in intracellular signal transduction. Studies using genetic ablation or pharmacologic inhibitors of different PI3K isoforms, in particular the class I PI3Kδ and PI3Kγ, have contributed to a greater understanding of the roles of these kinases in the modulation of inflammatory and immune responses. Recent data suggest that PI3Ks are also involved in the pathogenesis of acute pancreatitis. Activation of the PI3K signaling pathway, and in particular of the class IB PI3Kγ isoform, has a significant role in those events which are necessary for the initiation of acute pancreatic injury, namely calcium signaling alteration, trypsinogen activation, and nuclear factor-κB transcription. Moreover, PI3Kγ is instrumental in modulating acinar cell apoptosis, and regulating local neutrophil infiltration and systemic inflammatory responses during the course of experimental acute pancreatitis. The availability of PI3K inhibitors selective for specific isoforms may provide new valuable therapeutic strategies to improve the clinical course of this disease. This article presents a brief summary of PI3K structure and function, and highlights recent advances that implicate PI3Ks in the pathogenesis of acute pancreatitis.
Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Humans; Isoenzymes; Molecular Targeted Therapy; Pancreas; Pancreatitis; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Protein Conformation; Protein Kinase Inhibitors; Signal Transduction; Structure-Activity Relationship
PubMed: 25386068
DOI: 10.3748/wjg.v20.i41.15190 -
Biochimica Et Biophysica Acta Jun 2016In a recent study we explored Group-1-p21-activated kinases (GP.1-PAKs) in rat pancreatic acini. Only PAK2 was present; it was activated by...
In a recent study we explored Group-1-p21-activated kinases (GP.1-PAKs) in rat pancreatic acini. Only PAK2 was present; it was activated by gastrointestinal-hormones/neurotransmitters and growth factors in a PKC-, Src- and small-GTPase-mediated manner. PAK2 was required for enzyme-secretion and ERK/1-2-activation. In the present study we examined PAK2's role in CCK and TPA-activation of important distal signaling cascades mediating their physiological/pathophysiological effects and analyzed its role in pathophysiological processes important in early pancreatitis. In rat pancreatic acini, PAK2-inhibition by the specific, GP.1.PAK-inhibitor, IPA-3-suppressed cholecystokinin (CCK)/TPA-stimulated activation of focal-adhesion kinases and mitogen-activated protein-kinases. PAK2-inhibition reversed the dual stimulatory/inhibitory effect of CCK/TPA on the PI3K/Akt/GSK-3β pathway. However, its inhibition did not affect PKC activation. PAK2-inhibition protected acini from CCK-induced ROS-generation; caspase/trypsin-activation, important in early pancreatitis; as well as from cell-necrosis. Furthermore, PAK2-inhibition reduced proteolytic-activation of PAK-2p34, which is involved in programmed-cell-death. To ensure that the study did not only rely in the specificity of IPA-3 as a PAK inhibitor, we used two other approaches for PAK inhibition, FRAX597 a ATP-competitive-GP.1-PAKs-inhibitor and infection with a PAK2-dominant negative(DN)-Advirus. Those two approaches confirmed the results obtained with IPA-3. This study demonstrates that PAK2 is important in mediating CCK's effect on the activation of signaling-pathways known to mediate its physiological/pathophysiological responses including several cellular processes linked to the onset of pancreatitis. Our results suggest that PAK2 could be a new, important therapeutic target to consider for the treatment of diseases involving deregulation of pancreatic acinar cells.
Topics: Acinar Cells; Animals; Cell Death; Enzyme Activation; Male; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley; Signal Transduction; p21-Activated Kinases
PubMed: 26912410
DOI: 10.1016/j.bbadis.2016.02.008 -
World Journal of Gastroenterology Apr 2006Acute pancreatitis is generally believed to be a disease in which the pancreas is injured by digestive enzymes that it normally produces. Most of the potentially harmful... (Review)
Review
Acute pancreatitis is generally believed to be a disease in which the pancreas is injured by digestive enzymes that it normally produces. Most of the potentially harmful digestive enzymes produced by pancreatic acinar cells are synthesized and secreted as inactive zymogens which are normally activated only upon entry into the duodenum but, during the early stages of acute pancreatitis, those zymogens become prematurely activated within the pancreas and, presumably, that activation occurs within pancreatic acinar cells. The mechanisms responsible for intracellular activation of digestive enzyme zymogens have not been elucidated with certainty but, according to one widely recognized theory (the "co-localization hypothesis"), digestive enzyme zymogens are activated by lysosomal hydrolases when the two types of enzymes become co-localized within the same intracellular compartment. This review focuses on the evidence supporting the validity of the co-localization hypothesis as an explanation for digestive enzyme activation during the early stages of pancreatitis. The findings, summarized in this review, support the conclusion that co-localization of lysosomal hydrolases with digestive enzyme zymogens plays a critical role in permitting the intracellular activation of digestive enzymes that leads to acinar cell injury and pancreatitis.
Topics: Acute Disease; Amylases; Animals; Cathepsin B; Enzyme Activation; Enzyme Precursors; Humans; Hydrolases; Lysosomes; Pancreas; Pancreatitis; Protein Transport; Trypsinogen
PubMed: 16610045
DOI: 10.3748/wjg.v12.i13.1985 -
Journal of Dairy Science Nov 1983The effect of age and weaning on enzyme activities of abomasum and pancreas of the lamb was studied. Sixty-nine lambs were either maintained at the preruminant stage...
The effect of age and weaning on enzyme activities of abomasum and pancreas of the lamb was studied. Sixty-nine lambs were either maintained at the preruminant stage until 42 days of age or weaned between 20 and 30 days. They were slaughtered between birth and 100 days, and the mucosa of their abomasum and their pancreas were collected. At 2 days of age there was a threshold of glandular growth and of development of enzyme secretory potentialities. Pancreas showed an extensive hyperplasia without growth until day 2; its weight increased after day 7 but only by hypertrophy. Quantities of gastric enzymes in relation to empty live weight increased between birth and 2 days, but that of chymosin then decreased, whereas pepsin did not change significantly; effects of weaning were similar. The evolution of pancreatic enzyme activity was usually the reverse of that of chymosin; however, trypsin activity was low at birth and that of colipase did not increase at weaning. The ratio of colipase to lipase was always higher than 1, showing that lipase always was saturated in the lamb. The pancreas seemed to take over the secretion of abomasal proteolytic enzymes. Potentialities of enzyme digestion appeared to be influenced mainly by the age or weight of the animal; these potentialities were minimal for at least several days during the first neonatal week and, if there was enzymatic adaptation to the amounts of the ingested substrate, it did not occur rapidly.
Topics: Abomasum; Aging; Amylases; Animals; Chymosin; Chymotrypsin; Diet; Lipase; Pancreas; Pepsin A; Sheep; Trypsin; Weaning
PubMed: 6197430
DOI: 10.3168/jds.S0022-0302(83)82095-5 -
Amino Acids May 2009Cysteine catabolism in mammals is dependent upon cysteine dioxygenase (CDO), an enzyme that adds molecular oxygen to the sulfur of cysteine, converting the thiol to a... (Review)
Review
Cysteine catabolism in mammals is dependent upon cysteine dioxygenase (CDO), an enzyme that adds molecular oxygen to the sulfur of cysteine, converting the thiol to a sulfinic acid known as cysteinesulfinic acid (3-sulfinoalanine). CDO is one of the most highly regulated metabolic enzymes responding to diet that is known. It undergoes up to 45-fold changes in concentration and up to 10-fold changes in catalytic efficiency. This provides a remarkable responsiveness of the cell to changes in sulfur amino acid availability: the ability to decrease CDO activity and conserve cysteine when cysteine is scarce and to rapidly increase CDO activity and catabolize cysteine to prevent cytotoxicity when cysteine supply is abundant. CDO in both liver and adipose tissues responds to changes in dietary intakes of protein and/or sulfur amino acids over a range that encompasses the requirement level, suggesting that cysteine homeostasis is very important to the living organism.
Topics: Adipose Tissue; Animals; Cysteine; Cysteine Dioxygenase; Duodenum; Homeostasis; Kidney; Liver; Pancreas
PubMed: 19011731
DOI: 10.1007/s00726-008-0202-y -
Proceedings of the National Academy of... Dec 1985The stochastic boundary molecular dynamics method is used to study the structure, dynamics, and energetics of the solvated active site of bovine pancreatic ribonuclease...
The stochastic boundary molecular dynamics method is used to study the structure, dynamics, and energetics of the solvated active site of bovine pancreatic ribonuclease A. Simulations of the native enzyme and of the enzyme complexed with the dinucleotide substrate CpA and the transition-state analog uridine vanadate are compared. Structural features and dynamical couplings for ribonuclease residues found in the simulation are consistent with experimental data. Water molecules, most of which are not observed in crystallographic studies, are shown to play an important role in the active site. Hydrogen bonding of residues with water molecules in the free enzyme is found to mimic the substrate-enzyme interactions of residues involved in binding. Networks of water stabilize the cluster of positively charged active site residues. Correlated fluctuations between the uridine vanadate complex and the distant lysine residues are mediated through water and may indicate a possible role for these residues in stabilizing the transition state.
Topics: Animals; Binding Sites; Cattle; Hydrogen Bonding; Ions; Models, Molecular; Motion; Pancreas; Ribonucleases; Water; X-Ray Diffraction
PubMed: 3866234
DOI: 10.1073/pnas.82.24.8458