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)

The stimulation of sensory nerves by capsaicin exhibits the protective effect against caerulein-induced pancreatitis whereas deactivation of these nerves aggravates pancreatic damage evoked by overdose of caerulein. Calcitonin-gene related peptide (CGRP) has been identified as the prominent mediator of sensory nerves. The aim of the present study was to examine the influence of CGRP on the course of caerulein-induced pancreatitis (CIP). CIP led to a significant decrease in DNA synthesis and pancreatic blood flow (PBF) by 48% and 50% respectively, as well as a significant increase of pancreatic weight, plasma amylase concentration and development of the histological signs of pancreatic damage expressed as edema, leukocyte infiltration and vacuolization. Treatment with CGRP (2 x 10 micrograms/kg s.c.) attenuated the pancreatic tissue damage in caerulein-induced pancreatitis and completely reversed the deleterious effect of the ablation of sensory nerves on caerulein-induced pancreatitis. We conclude that CGRP exerts protective effect against caerulein-induced pancreatitis and is able to reverse the damage caused by deactivation of sensory nerves. Vasodilatation and preservation of pancreatic blood flow are involved in this effect.
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PMID:Protective effect of calcitonin gene-related peptide against caerulein-induced pancreatitis in rats. 944 24

1. After monitoring the changes associated with necrotizing acute pancreatitis in rats from early stages to 24 h after infusion of 5% sodium taurocholate in the choledocus, we characterized by flow cytometry the zymogen granules that still remained in the pancreas 18 h after sodium taurocholate infusion in order to explore whether alterations in the enzyme content and/or in the composition of the granule membrane could be related to the intracellular mechanisms involved in the development of necrotizing acute pancreatitis. 2. Significant increases in the haematocrit, plasma and peritoneal exudate amylase levels and oedema were observed from the third hour after 5% sodium taurocholate infusion onwards. Additionally, cell alterations such as hypergranulation, dilatation of the endoplasmic reticulum and autophagic vacuoles were found 3 and 6 h after infusion. DNA decrease, degranulation and necrosis were observed from 12 h after sodium taurocholate infusion onwards. 3. Flow cytometric measurements of zymogen granules isolated from rat pancreas 18 h after 5% sodium taurocholate infusion revealed a significant decrease in their internal complexity without major changes in their size. Double staining of granules with Tetragonolobus purpureus lectin, which specifically binds L-fucose and specific anti-trypsinogen or anti-amylase antisera, showed that rats with induced pancreatitis have decreased amounts of L-fucose in the membrane glycoconjugates and lower enzyme content (70% and 30% less for trypsinogen and amylase respectively). 4. A decrease in L-fucose in the membrane together with membrane abnormalities observed by electron microscopy in zymogen granules isolated 18 h after sodium taurocholate infusion indicate an altered synthesis of new granules or lysis of preformed zymogen granules which would favour differential loss of granular enzymes, mainly trypsinogen, which in turn could increase the severity of disease.
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PMID:Changes in both the membrane and the enzyme content of individual zymogen granules are associated with sodium taurocholate-induced pancreatitis in rats. 961 64

Hereditary pancreatitis (OMIM 167800) is thought to be associated with a mutation of the exon 3 of cationic trypsinogen (Nature Genet (1996): 14:141-145). This paper reports sequence data of two independent families suffering from this disease. PCR amplificates from leukocyte or buccal swab DNA showed no mutation of exon 3 of cationic trypsinogen. Instead, in exon 2, an A-to-T tranversion was found that led to the substitution of Asn by Ile in the sixth amino acid of the active trypsin. In exons 4 and 5, silent mutations were found. In the other expressed trypsinogens, several homozygous alterations not associated to hereditary pancreatitis were identified. As a model of pathogenesis, we hypothesize that mutation of trypsinogen in exon 2 could lead to premature cleavage of the activation peptide of trypsinogen or to altered intracellular transport.
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PMID:Mutations of the cationic trypsinogen in hereditary pancreatitis. 963 18

Carcinogens present in cigarette smoke and diet have been associated with pancreatic cancer. We hypothesized that heterocyclic and aromatic amines implicated in these exposures could be involved as causative agents and that therefore genetic variation in enzymes metabolizing these carcinogens could modify the risk of developing malignant and benign pancreatic disease. The effect of the genetic polymorphism of acetyltransferases (NAT1) and NAT2), glutathione S-transferase M1 (GSTM1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) on the risk of pancreatic diseases (cancer, pancreatitis) was examined in a case-control study. PCR-based assays were used for genotype analysis of genomic DNA from whole blood cells. Samples collected from Caucasian patients with diagnosed pancreatic cancer (n = 81), with non-alcoholic (n = 41) and alcoholic pancreatitis (n = 73) and from asymptomatic control subjects (n = 78) were analysed. The prevalence of GSTM1 null genotype and of NAT2 fast and slow acetylator genotypes and the distribution of frequencies for NQO1 genotypes did not differ in subjects with pancreatic diseases vs controls. For NAT1 slow acetylators a non-significant excess (P = 0.18) was found among pancreatic cancer cases vs controls. There was a significant over-representation of the GSTM1 AB or B genotype in all pancreatic disease cases combined (OR = 2.6; P < 0.05). When concurrent controls were pooled with literature controls (n = 1427), OR was 1.4 (P = 0.08). The results of this study, requiring confirmation, suggest that the polymorphism of GSTM1 and NAT1 enzymes may be associated with a modest increase in susceptibility to pancreatic diseases.
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PMID:Genetic polymorphism of N-acetyltransferases, glutathione S-transferase M1 and NAD(P)H:quinone oxidoreductase in relation to malignant and benign pancreatic disease risk. The International Pancreatic Disease Study Group. 988 82

The aim of this study was to test the hypothesis that apoptosis can protect against experimental pancreatitis and induction of apoptosis by an extract of Artemisia asiatica (DA-9601) is beneficial in cerulein-induced pancreatis in rats. Pancreatitis was induced in 6-week-old male SPF Sprague-Dawley rats by two intravenous (i.v.) administrations of 40 microg/kg cerulein. To investigate the effects of DA-9601 on the severity of pancreatitis and extent of apoptosis, rats were treated with intragastric DA-9601, 30 mg/kg (D30), 100 mg/kg (D100), or 300 mg/kg (D300), intraperitoneal superoxide dismutase, 10,000 U/kg (SOD), and i.v. gabexate mesilate, 40 mg/kg (Foy), three times (30 min before cerulein injection, 30 and 90 min after cerulein injection). The control group was administered vehicle alone. Ten rats were included in each treatment group and control group. Rats were sacrificed 5 h after cerulein treatment. Serum amylase, histological activity index (HAI), pancreatic lipid peroxide levels, and apoptotic index [in situ hybridization by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL)] were determined. Gel electrophoresis was performed for the presence of DNA fragmentations. The results were as follows. Serum amylase was significantly increased in all cerulein-treated groups compared to normal controls (p < 0.001). The HAI was significantly decreased in only the D300 group compared to the controls (p < 0.05). The apoptotic index of the cerulein-alone group was 3.8 +/- 2.7, but the mean apoptotic indexes of the SOD and Foy groups were 16.4 +/- 4.6 and 13.3 +/- 1.8, respectively, a significant increase (p < 0.01). The apoptotic index was more significantly increased in the DA-9601-treated groups, dose dependently (8.4 +/- 3.4 in D30, 14.8 +/- 4.3 in D100, 24.2 +/- 4.7 in D300). A smearing pattern of DNA electrophoresis was noted in the DA-9601-treated groups. In conclusion, DA-9601, an extract of Artemisia, induced apoptosis of pancreatic acinar cells dose dependently and concomitantly attenuated the severity of pancreatitis.
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PMID:Induction of apoptosis with an extract of Artemisia asiatica attenuates the severity of cerulein-induced pancreatitis in rats. 970 Sep 46

Although a reduction in peripheral lymphocytes has been reported in clinical cases of acute pancreatitis, the thymic change remains still unknown. To investigate impairment of cellular immunity in acute pancreatitis, alterations of the thymus in rats with acute pancreatitis were examined experimentally. Male Wistar rats were used. Two groups with pancreatitis of different severity and a control group for each were established. The thymus was weighed and the number of thymocytes counted. Apoptosis in the thymus was examined by in situ nick-end labeling, DNA agarose gel electrophoresis, and cell cycle analysis using propidium iodide. Both thymus weight and number of thymocytes decreased significantly in the rats with necrotizing pancreatitis 20 h after induction of pancreatitis (P <0.02 vs sham operation). Neither thymus atrophy nor thymocyte reduction was observed in rats with edematous pancreatitis. In thymuses from rats with necrotizing pancreatitis, in situ nick-end labeling showed a significant increase in apoptotic changes of thymocytes, which was also confirmed by the stepladder pattern on agarose gel electrophoresis of the extracted DNA and by cell cycle analysis. It is concluded that thymus atrophy associated with apoptosis occurs in rats with necrotizing pancreatitis.
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PMID:Thymic atrophy caused by thymocyte apoptosis in experimental severe acute pancreatitis. 973 25

Production of inflammatory cytokines in the pancreas, lung, and liver is believed to play a major role in the development of severe pancreatitis. This tissue-specific production could lend itself to directed anti-cytokine gene therapy if an appropriate delivery system could be developed. This study was undertaken to examine a novel approach for the delivery of protein-based therapies to the tissues involved during acute pancreatitis. Healthy mice received an intraperitoneal injection of cationic liposomes and a DNA plasmid containing the chloramphenicol acetyltransferase (CAT) reporter gene. Animals were killed at 12 hours and 1, 2, 3, 7, and 14 days with serum, pancreas, lung, and liver harvested. Acute pancreatitis was induced (cerulein, 50 micrograms/kg/hr intraperitoneally x4) in additional mice before or after CAT transfection. The presence of pancreatitis was established in all animals by histologic scoring of pancreata and by serum amylase and lipase levels. CAT transfection efficiency was determined by quantitative CAT enzyme activity within tissue homogenates. Animals that received the liposome were successfully transfected with the CAT gene into the pancreas, lungs, and liver. Maximal transfection in each tissue occurred at 12 hours with decreasing CAT activity over the ensuing 14 days. No healthy animals receiving the CAT gene developed elevations in amylase, lipase, or any histologic parameter of pancreatitis. Transfection efficiency in the pancreas was markedly increased by preexisting or delayed induction of pancreatitis, whereas transfection of the lung and liver was increased to a lesser extent. Gene transfection into the pancreas, liver, and lungs is possible using a cationic liposome delivery system that does not induce pancreatitis or pancreatic inflammation. Pancreatic expression of the gene product is equal to or greater than that of the organs of the reticuloendothelial system and continues at very high efficiency rates during acute pancreatitis.
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PMID:Cationic liposome-mediated gene transfer during acute pancreatitis: tissue specificity, duration, and effects of acute inflammation. 984 74

The mechanisms responsible for intrapancreatic digestive enzyme activation as well as the relationship between that activation and cell injury during pancreatitis are not understood. We have employed an in vitro system in which freshly prepared pancreatic acini are exposed to a supramaximally stimulating concentration of the CCK analog caerulein to explore these issues. We find that in vitro trypsinogen activation depends on the continued presence of Ca2+ in the suspending medium and that it is half-maximal in the presence of 0.3 mM Ca2+. Caerulein-induced trypsinogen activation can be halted by removal of Ca2+ from the suspending medium or by chelation of intracellular Ca2+. Increasing intracellular Ca2+ with either ionomycin or thapsigargin does not induce trypsinogen activation. We have monitored cell injury by measuring the leakage of lactate dehydrogenase (LDH) from acini and by quantitating intercalation of propidium iodide (PI) into DNA. Leakage of LDH and intercalation of PI in response to supramaximal stimulation with caerulein can be detected only after caerulein-induced trypsinogen activation has already occurred, and these indications of cell injury can be prevented by addition of a cell-permeant protease inhibitor. Our findings indicate that caerulein-induced intra-acinar cell activation of trypsinogen depends on a rise in intracellular Ca2+, which reflects entry of Ca2+ from the suspending medium. Intra-acinar cell activation of trypsinogen is an early as well as a critical event in pancreatitis. The subsequent cell injury in this model is mediated by activated proteases.
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PMID:Secretagogue-induced digestive enzyme activation and cell injury in rat pancreatic acini. 1019 25

Controlled clinical trials in renal transplantation have demonstrated that mycophenolate mofetil is well tolerated and has lower renal transplant rejection rates than azathioprine regimens. This study reports on the clinical experiences at two institutions with mycophenolate mofetil (MMF) for severe lupus nephritis. Twelve patients with relapsing or resistant nephritis previously treated with cyclophosphamide therapy and one patient who refused cyclophosphamide as initial therapy for diffuse proliferative nephritis but accepted MMF were included. During combined MMF/prednisone therapy, serum creatinine values remained normal or declined from elevated values: mean change in serum creatinine was -0.26+/-0.46 microM/L, P = 0.039. Proteinuria significantly decreased: mean change in urine protein-to-creatinine ratios was -2.53+/-3.76, P = 0.039. Decreased serum complement component C3 and elevated anti-double-stranded DNA antibody levels at baseline improved in some, but not all, patients. The mean initial dose of MMF was 0.92 g/d (range, 0.5 to 2 g/d). The mean duration of therapy was 12.9 mo (range, 3 to 24 mo). Adverse events included herpes simplex stomatitis associated with severe leukopenia (n = 1), asymptomatic leukopenia (n = 2), nausea/ diarrhea (n = 2), thinning of scalp hair (n = 1), pancreatitis (n = 1), and pneumonia without leukopenia (n = 1). Recurrence of the pancreatitis led to discontinuation of MMF in this patient; all other adverse events resolved with dose reduction. It is concluded that MMF is well tolerated and has possible efficacy in controlling major renal manifestations of systemic lupus erythematosus. Controlled clinical trials are needed to define the role of MMF in the management of lupus nephritis.
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PMID:Mycophenolate mofetil therapy in lupus nephritis: clinical observations. 1020 68

Epidermal growth factor (EGF) exhibits gastroprotective and ulcer-healing action. These observations prompted us to determine the influence of EGF on cerulein-induced pancreatitis (CIP) in the rat. Acute pancreatitis was induced by subcutaneous infusion of cerulein (10 microg/kg/h) for 5 h. Initially EGF was administrated twice at doses of 1, 5, 10 or 100 microg/kg s.c. (first injection 30 min prior to cerulein infusion, and the second injection 2.5 h after the start of cerulein infusion) and from this part of study 10 microg/kg was chosen for the next experiments. CIP led to a significant decrease in DNA synthesis and a reduction in pancreatic blood flow (PBF) by 42 and 30%, respectively, as well as a significant increase in pancreatic weight, plasma amylase concentration, plasma interleukin-1beta (IL-1beta) level and the development of the histological signs of pancreatic damage with marked edema, leukocyte infiltration and vacuolization of acinar cells. Treatment with EGF attenuated the pancreatic tissue damage in CIP as manifested by partial reversal of the drop in DNA synthesis and improvement of pancreatic histology. Moreover, EGF administration attenuated the fall in PBF and significantly reduced the cerulein-evoked increase in pancreatic weight. Also plasma amylase and IL-1beta were decreased in rats treated with EGF. We conclude that: (1) EGF exerts a protective effect against CIP, and (2) the beneficial activity of EGF in CIP seems to depend on the increase in pancreatic cell proliferation, the reduction in cytokine generation and the attenuation of the fall in PBF.
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PMID:Epidermal growth factor protects against pancreatic damage in cerulein-induced pancreatitis. 1039 25


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