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)

This study assessed the efficacy of pancreatic surface delivered enkephalin (ENK)-encoding herpes simplex virus type 1 (HSV-1) on spontaneous behaviors and spinal cord and pancreatic enkephalin expression in an experimental pancreatitis model. Replication-defective HSV-1 with proenkephalin complementary DNA (cDNA) (HSV-ENK) or control beta-galactosidase cDNA (HSV-beta-gal), or media vehicle (Veh) was applied to the pancreatic surface of rats with dibutyltin dichloride (DBTC)-induced pancreatitis. Spontaneous exploratory behavioral activity was monitored on days 0 and 6 post DBTC and vector treatments. The pancreas, thoracic dorsal root ganglia (DRG, T9-10), and spinal cord (T9-10) were immunostained for met-enkephalin (met-ENK), beta-gal, and HSV-1 proteins. Spinal cord was also immunostained for c-Fos, and pancreas was stained for the inflammatory marker regulated on activation, normal T-cells expressed and secreted (RANTES), mu-opioid receptor, and hemotoxylin/eosin. On day 6, compared to pancreatitis and vector controls, the DBTC/HSV-ENK treated rats had significantly improved spontaneous exploratory activities, increased met-ENK staining in the pancreas and spinal cord, and normalized c-Fos staining in the dorsal horn. Histopathology of pancreas in DBTC/HSV-ENK treated rats showed preservation of acinar cells and cytoarchitecture with minimal inflammatory cell infiltrates, compared to severe inflammation and acinar cell loss seen in DBTC/HSV-beta-gal and DBTC/Veh treated rats. Targeted transgene delivery and met-ENK expression successfully produced decreased inflammation in experimental pancreatitis.
Mol Ther 2007 Oct
PMID:Treatment of inflamed pancreas with enkephalin encoding HSV-1 recombinant vector reduces inflammatory damage and behavioral sequelae. 1756 49

Quantitative fluorescent multiplex PCR (QFM-PCR) was established in order to make possible the rapid and efficient mutational analysis of the pancreatic secretory trypsin inhibitor (SPINK1) gene. Using QFM-PCR, a novel heterozygous deletion encompassing the entire SPINK1 gene was identified in one of nine newly recruited French Caucasian families with chronic pancreatitis. The breakpoints were fully characterized and the approximately 30 kb deletion was termed c.1-15969_c.240+7702del30588bp. Whilst sequences with the potential to form non-B DNA structures were found to span both the 5' and 3' deletion breakpoints, the generation of this gross deletion is potentially explicable in terms of non-homologous end-joining facilitated by the presence of a 1-bp microhomology at the two ends. The SPINK1 gene deletion identified in the index patient was also detected in her affected father and paternal uncle but not in 50 healthy French Caucasians. Remarkably, in all three affected individuals, the SPINK1 deletion was found to be co-inherited with a heterozygous p.L997F missense mutation in the unlinked CFTR gene, a lesion previously reported to be associated with a variety of cystic fibrosis-related diseases including idiopathic pancreatitis. Given that the SPINK1 deletion constitutes a clear-cut disease-causing factor, it may be that the CFTR missense mutation acts as a disease modifier in the context of this particular family.
Mol Genet Metab
PMID:Co-inheritance of a novel deletion of the entire SPINK1 gene with a CFTR missense mutation (L997F) in a family with chronic pancreatitis. 1768 20

Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive inherited disorder, characterized by marked hypertriglyceridemia, eruptive xanthoma, hepatosplenomegaly, recurrent attacks of pancreatitis, and markedly low or absent LPL activity in postheparin plasma. A majority of LPL deficient patients have been reported to have point mutations in the LPL gene; however, we find a complex deletion-insertion mutation by Alu elements, mobile retrotransposons, in a patient with LPL deficiency. This patient suffered from acute pancreatitis, showed chylomicronemia and lacked detectable LPL activity or mass in her postheparin plasma. Southern blot analysis and long-range PCR of the patient's DNA demonstrated a 2.2-kb deletion encompassing exon 2. Sequence analysis revealed (1) a 2.3-kb deletion between an AT-rich region adjacent to an Alu element in intron 1 and another Alu element in intron 2; (2) an insertion of approximately 150bp 5'-truncated Alu sequence with a poly (A) tail at the deletion point. The inserted sequence belongs to Alu Yb9, the youngest subfamily of Alu elements. The deletion occurred at the consensus cleavage site (3'-A|TTTT-5') without target site duplication. These findings indicated that Alu retrotransposition caused the complex deletion-insertion. The patient was homozygous for this complex mutation, which eliminates exon 2 and leads to LPL deficiency. To our knowledge, the patient is the first case with LPL deficiency due to a complex deletion-insertion mediated by Alu repetitive elements.
Mol Genet Metab 2007 Nov
PMID:A novel complex deletion-insertion mutation mediated by Alu repetitive elements leads to lipoprotein lipase deficiency. 1770 45

The clinical distinction between cancer and chronic pancreatitis is difficult in patients with pancreatic masses. To test whether detection of aberrant serum DNA could assist in this important differential diagnosis, we tested a panel of 12 microsatellitemarkers from chromosomes 17p, 17q, 13q, 9p, 5q, and 2p in the blood of 35 pancreatic cancer patients, 22 patients with chronic pancreatitis, and 20 healthy individuals. An average of 2.8 loss of heterozygosity (LOH) was found in 32 of 35 cancer patients of whom 30 (86%) had 2 or more LOH. LOH was also found in 7 of 22 pancreatitis patients but all these patients had only 1 LOH. No LOH was detected in healthy donors of comparable age. These data suggest that LOH analysis may be a substantial help for diagnosing pancreatic masses. An extension of the panel, perhaps in combination with a better selection of markers may further improve this assay.
Diagn Mol Pathol 2007 Sep
PMID:Microsatellite analysis in serum DNA as a diagnostic tool for distinction of patients with unknown pancreatic masses. 1772 26

Increase in the number of intrapancreatic sensory nerve fibers has been implicated in the generation of pain in chronic pancreatitis. Because some sensory neurotransmitters (e.g., substance P) are known to have proinflammatory effects, we hypothesized that denervation of intrapancreatic nerves might influence not only pain generation but also inflammation. Neonatal Lewis rats were injected with capsaicin (50 mg/kg or 0 mg/kg), a neurotoxin, to induce denervation of primary sensory neurons. When rats reached 170-190 g body weight, experimental pancreatitis was induced by a single administration of dibutyltin dichloride (7 mg/mg). The severity of pancreatitis was evaluated in both groups in the acute phase (at 3 and 7 days) and chronic phase (at 28 days). At day 7, the sensory denervation induced by neonatal capsaicin administration inhibited pancreatic inflammation on both histological (determination of interstitial edema, expansion of interlobular septa and intercellular spaces, and inflammatory cell infiltration) and biochemical (intrapancreatic myeloperoxidase activity) evaluation. Furthermore, at day 28, glandular atrophy, pseudotubular complexes, and rate of fibrosis were each significantly lower in the capsaicin-pretreated group than in the vehicle-pretreated group. Our findings provide in vivo evidence that primary sensory neurons play important roles in both acute pancreatitis and chronic pancreatic inflammation with fibrosis.
Med Mol Morphol 2007 Sep
PMID:Effects of sensory denervation by neonatal capsaicin administration on experimental pancreatitis induced by dibutyltin dichloride. 1787 46

The major keratins in the pancreas and liver are keratins 8 and 18 (K8/K18), but their function seemingly differs in that liver K8/K18 are essential cytoprotective proteins, whereas pancreatic K8/K18 are dispensable. This functional dichotomy raises the hypothesis that K8-null pancreata may undergo compensatory cytoprotective gene expression. We tested this hypothesis by comparing the gene expression profile in pancreata of wild-type and K8-null mice. Most prominent among the up-regulated genes in K8-null pancreas was mRNA for regenerating islet-derived (Reg)-II, which was confirmed by quantitative reverse transcription-polymerase chain reaction and by an anti-Reg-II peptide antibody we generated. Both K8-null and wild-type mice express Reg-II predominantly in acinar cells as determined by in situ hybridization and immunostaining. Analysis of Reg-II expression in various keratin-related transgenic mouse models showed that its induction also occurs in response to keratin cytoplasmic filament collapse, absence, or ablation of K18 Ser52 but not Ser33 phosphorylation via Ser-to-Ala mutation, which represent situations associated with predisposition to liver but not pancreatic injury. In wild-type mice, Reg-II is markedly up-regulated in two established pancreatitis models in response to injury and during the recovery phase. Thus, Reg-II is a likely mouse exocrine pancreas cytoprotective candidate protein whose expression is regulated by keratin filament organization and phosphorylation.
Mol Biol Cell 2007 Dec
PMID:Reg-II is an exocrine pancreas injury-response product that is up-regulated by keratin absence or mutation. 1789 82

Suprastimulation of pancreatic acini is a well-known model for pancreatitis, and it is characterized by actin reorganization and cell blebbing. Currently, however, the mechanisms underlying regulation of these aberrant cytoskeletal and membrane dynamics and how they contribute to cell injury are unclear. We observed that suprastimulation results in a rapid activation of Src and relocalization of the actin-binding protein cortactin from the apical to the basolateral domain at the necks of membrane blebs. Furthermore, Src-mediated cortactin tyrosine phosphorylation was markedly increased after suprastimulation. Pretreatment of acini with Src inhibitors or expression of a cortactin tyrosine phospho-inhibitory mutant reduced actin redistribution and bleb formation induced by suprastimulation in vitro. Importantly, inhibition of Src activity in rat models of suprastimulation-induced pancreatitis substantially reduced disease severity, as indicated by a reduction in serum amylase and pancreatic edema and a striking improvement in tissue histology. These findings indicate a novel, disease-relevant role for Src-mediated cortactin phosphorylation in aberrant reorganization of the actin cytoskeleton, a mechanism that is likely to have implications in other types of cell injury. In addition, they suggest a potential use for Src inhibitors as an approach to reduce cell injury.
Mol Biol Cell 2008 May
PMID:Src-mediated cortactin phosphorylation regulates actin localization and injurious blebbing in acinar cells. 1835 71

Vacuole membrane protein 1 (Vmp1) is membrane protein of unknown molecular function that has been associated with pancreatitis and cancer. The social amoeba Dictyostelium discoideum has a vmp1-related gene that we identified previously in a functional genomic study. Loss-of-function of this gene leads to a severe phenotype that compromises Dictyostelium growth and development. The expression of mammalian Vmp1 in a vmp1(-) Dictyostelium mutant complemented the phenotype, suggesting a functional conservation of the protein among evolutionarily distant species and highlights Dictyostelium as a valid experimental system to address the function of this gene. Dictyostelium Vmp1 is an endoplasmic reticulum protein necessary for the integrity of this organelle. Cells deficient in Vmp1 display pleiotropic defects in the secretory pathway and organelle biogenesis. The contractile vacuole, which is necessary to survive under hypoosmotic conditions, is not functional in the mutant. The structure of the Golgi apparatus, the function of the endocytic pathway and conventional protein secretion are also affected in these cells. Transmission electron microscopy of vmp1(-) cells showed the accumulation of autophagic features that suggests a role of Vmp1 in macroautophagy. In addition to these defects observed at the vegetative stage, the onset of multicellular development and early developmental gene expression are also compromised.
Mol Biol Cell 2008 Aug
PMID:Vacuole membrane protein 1 is an endoplasmic reticulum protein required for organelle biogenesis, protein secretion, and development. 1855 Jul 98

Hypertriglyceridemia is a common complex metabolic trait that is associated with increased atherosclerosis risk, presence of the metabolic syndrome and, with extreme elevation, increased risk of pancreatitis. Hierarchical cluster analysis using clinical and biochemical features of the Frederickson hyperlipoproteinemia types can generate hypotheses for molecular genetic studies. High throughput resequencing of individuals at the extremes of plasma triglyceride concentration has shown that both rare genetic variants with large effects and common genetic variants with moderate effects explain a relatively large proportion of variation. Very recent progress using high-density sets of genome-wide markers have identified additional genetic determinants of plasma triglyceride concentrations, albeit within largely normolipidemic subjects and with small effect sizes. Phenomic evaluation of patients with hypertriglyceridemia might help to clarify genotype-phenotype correlations and responses to interventions.
Mol Cell Biochem 2009 Jun
PMID:Hypertriglyceridemia: phenomics and genomics. 1913 Jan 80

The factors necessary for normal pancreatic islet morphogenesis have not been well characterized. Here we report that connective tissue growth factor (CTGF) is involved in the establishment of normal islet endocrine cell ratio and architecture. CTGF is a secreted protein known to modulate several growth factor-signaling pathways including TGF-beta, BMP, and Wnt. Although its role in pancreatic diseases such as pancreatitis and pancreatic cancer are well documented, a role for CTGF in normal pancreas development and function has heretofore not been examined. Using a lacZ-tagged CTGF allele, we describe for the first time the expression pattern of CTGF in the developing pancreas and the requirement of CTGF for normal islet morphogenesis and embryonic beta-cell proliferation. CTGF is highly expressed in pancreatic ductal epithelium and vascular endothelium, as well as at lower levels in developing insulin(+) cells, but becomes down-regulated in beta-cells soon after birth. Pancreata from CTGF null embryos have an increase in glucagon(+) cells with a concomitant decrease in insulin(+) cells, and show defects in islet morphogenesis. Loss of CTGF also results in a dramatic decrease in beta-cell proliferation at late gestation. Unlike CTGF null embryos, CTGF heterozygotes survive past birth and exhibit a range of islet phenotypes, including an intermingling of islet cell types, increased number of glucagon(+) cells, and beta-cell hypertrophy.
Mol Endocrinol 2009 Mar
PMID:Connective tissue growth factor (CTGF) inactivation leads to defects in islet cell lineage allocation and beta-cell proliferation during embryogenesis. 1913 12


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