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)

Growth factors such as TGF-beta 1 and EGF are known to modulate the deposition of extracellular matrix components and tissue repair and to affect the cellular growth but their expression in the course of pancreatitis has not been studied. In this study we investigated the gene expression of TGF-beta 1 mRNA and EGF mRNA and other parameters of the pancreas including DNA synthesis, blood flow (PBF), tissue protein content and plasma amylase during the induction of acute pancreatitis. Supramaximal dose of cearulein (10 mg/kg/h s.c.) was infused for 5 h to induce pancreatitis. Animals were killed after 1, 2, 3, 4 and 5 h of infusion. The PBF was measured, blood samples were withdrawn to determine serum amylase concentration, biopsy samples were taken to measure the protein content and DNA synthesis. Expression of TGF-beta 1 and EGF mRNA was studied by reverse-transcription of polymerase chain reaction (RT-PCR). Caerulein infused caused a time-dependent decrease in DNA synthesis accompanied by gradual decrease of PBF and significant increase in pancreatic weight. The pancreatic protein content and plasma amylase showed progressive rise during 5 h of cearulein infusion. Histology revealed tissue edema, cellular vacuolization and prominent leukocyte infiltration after 3 h of cearulein infusion. TGF-beta 1 mRNA was strongly expressed at each time interval beginning from the 1 h after the start of cearulein infusion. In contrast, EGF mRNA was detected only at 5 h after induction of pancreatitis. We conclude that 1) the development of caerulein-induced pancreatitis results in the inhibition of pancreatic growth and the reduction in PBF accompanied by enhanced expression of TGF-beta 1; 2) The expression of EGF that was observed at the end of the induction of pancreatitis may indicate the initiation of pancreatic repair; 3) TGF-beta 1 seems to lead to subsequent induction of EGF that may stimulate the regeneration of injured pancreas.
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PMID:Expression of transforming growth factor-beta 1 and epidermal growth factor in caerulein-induced pancreatitis in rat. 909 26

The acinar cell culture plays a very important role in research of pancreatic pathophysiology. The aim of this study was to establish a long-term culture of human (foetal) pancreatic acinar cells in standardized nutrient media with supplements. Acinar cells were prepared from pancreatic tissues obtained from aborted foetus (> or =35 weeks) with no prior pancreatic complications by collagenase digestion and cultured using different media and supplements. The purity and phenotype of acinar cells was confirmed by various staining techniques and FACS. The acinar cell proliferation was determined at different time intervals by Bromo-deoxyuridine (BrdU) incorporation, and metabolic enzyme activity was analysed. The acini could be cultured and maintained in Ham's F-12 K/M199 media in the presence of 5% BSA, 0.1 mg/ml STI, 10 ng/ml EGF, and 10% FCS with the same morphological appearance as that of freshly prepared for 12 days with maximum viability of 80-85% and formation of monolayer without extracellular matrix. A significant BrdU incorporation of acinar cells in primary culture was observed which was maximum (105%) at day four. Higher amylase and lipase activity was seen in freshly isolated acinar cells which decreased with time of the culture. The established human pancreatic acinar cell culture may act as an excellent model to study exocrine dysfunction or pancreatitis in response to acinar cell injury.
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PMID:Primary culture of pancreatic (human) acinar cells. 1824 27

Pancreatic secretory trypsin inhibitor (PSTI) is expressed in most bladder carcinomas, where its pathophysiological relevance is unclear. Using recombinant normal sequence PSTI/tumor-associated trypsin inhibitor (TATI), a variant associated with familial pancreatitis (N34S), an active site-inactivated variant (R18/V19), and immunoneutralization and RNA interference-mediated knockdown techniques, we investigated the actions of PSTI/TATI on cell migration (wounding monolayers), collagen invasion (gel invasion assays), and proliferation (Alamar blue) on 253J, RT4, and HT1376 human bladder carcinoma cell lines. All three forms of PSTI/TATI stimulated migration twofold, and normal sequence PSTI/TATI showed synergistic promigratory effects when added with EGF. Addition of structurally unrelated soybean trypsin inhibitor had no promigratory activity. Similar results were seen using collagen invasion assays, although the active site mutated variant had no proinvasive activity, probably due to reduced Akt2 activation. PSTI/TATI did not stimulate proliferation despite acting, at least partially, through the EGF receptor, as effects of PSTI/TATI were truncated by the addition of an EGF receptor blocking antibody or the tyrosine kinase inhibitor tyrphostin. Cell lines produced endogenous PSTI/TATI, and PSTI/TATI RNA interference knockdown or the addition of PSTI/TATI, EGF receptor, or tyrphostin blocking agents reduced migration and invasion below baseline. PSTI/TATI induced phosphorylation of the EGF receptor, ERK1 and ERK2, Akt2 and Akt3, JNK1, MKK3, and ribosomal protein S6 kinase 1. This profile was more limited than that induced by EGF and did not include Akt1, probably explaining the lack of proproliferative activity. Our findings of autocrine stimulation and synergistic responses between EGF and PSTI/TATI at concentrations found in urine and tissue suggest that PSTI/TATI has pathophysiological relevance.
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PMID:Pancreatic secretory trypsin inhibitor causes autocrine-mediated migration and invasion in bladder cancer and phosphorylates the EGF receptor, Akt2 and Akt3, and ERK1 and ERK2. 2369 20

Although numerous genetic mutations and amplifications have been identified in pancreatic cancer, much of the molecular pathogenesis of the disease remains undefined. While proteomic and transcriptomic analyses have been utilized to probe and characterize pancreatic tumors, lipidomic analyses have not been applied to identify perturbations in pancreatic cancer patient samples. Thus, we utilized a mass spectrometry-based lipidomic approach, focused towards the sphingolipid class of lipids, to quantify changes in human pancreatic cancer tumor and plasma specimens. Subgroup analysis revealed that patients with positive lymph node metastasis have a markedly higher level of ceramide species (C16:0 and C24:1) in their tumor specimens compared to pancreatic cancer patients without nodal disease or to patients with pancreatitis. Also of interest, ceramide metabolites, including phosphorylated (sphingosine- and sphinganine-1-phosphate) and glycosylated (cerebroside) species were elevated in the plasma, but not the pancreas, of pancreatic cancer patients with nodal disease. Analysis of plasma level of cytokine and growth factors revealed that IL-6, IL-8, CCL11 (eotaxin), EGF and IP10 (interferon inducible protein 10, CXCL10) were elevated in patients with positive lymph nodes metastasis, but that only IP10 and EGF directly correlated with several sphingolipid changes. Taken together, these data indicate that sphingolipid metabolism is altered in human pancreatic cancer and associated with advanced disease. Assessing plasma and/or tissue sphingolipids could potentially risk stratify patients in the clinical setting.
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PMID:Altered sphingolipid metabolism in patients with metastatic pancreatic cancer. 2497 Jan 74

P-21-activated kinases (PAKs) are serine/threonine kinases comprising six isoforms divided in two groups, group-I (PAK1-3)/group-II (PAK4-6) which play important roles in cell cytoskeletal dynamics, survival, secretion and proliferation and are activated by diverse stimuli. However, little is known about PAKs ability to be activated by gastrointestinal (GI) hormones/neurotransmitters/growth-factors. We used rat pancreatic acini to explore the ability of GI-hormones/neurotransmitters/growth-factors to activate Group-I-PAKs and the signaling cascades involved. Only PAK2 was present in acini. PAK2 was activated by some pancreatic growth-factors [EGF, PDGF, bFGF], by secretagogues activating phospholipase-C (PLC) [CCK, carbachol, bombesin] and by post-receptor stimulants activating PKC [TPA], but not agents only mobilizing cellular calcium or increasing cyclic AMP. CCK-activation of PAK2 required both high- and low-affinity-CCK1-receptor-state activation. It was partially reduced by PKC- or Src-inhibition, but not with PI3K-inhibitors (wortmannin, LY294002) or thapsigargin. IPA-3, which prevents PAK2 binding to small-GTPases partially inhibited PAK2-activation, as well as reduced CCK-induced ERK1/2 activation and amylase release induced by CCK or bombesin. This study demonstrates pancreatic acini, possess only one Group-I-PAK, PAK2. CCK and other GI-hormones/neurotransmitters/growth-factors activate PAK2 via small GTPases (CDC42/Rac1), PKC and SFK but not cytosolic calcium or PI3K. CCK-activation of PAK2 showed several novel features being dependent on both receptor-activation states, having PLC- and PKC-dependent/independent components and small-GTPase-dependent/independent components. These results show that PAK2 is important in signaling cascades activated by numerous pancreatic stimuli which mediate their various physiological/pathophysiological responses and thus could be a promising target for the development of therapies in some pancreatic disorders such as pancreatitis.
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PMID:Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms. 2597 36