Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001339 (acute pancreatitis)
 10,593 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rising trend of idiopathic pancreatitis, and our demonstration that cytochromes P450 are 'induced' in most patients, prompted a search for enzyme inducers in their work environments. The findings in 19 patients (chronic pancreatitis 15, acute pancreatitis 4) are described. In the initial series of 12 consecutive patients with idiopathic pancreatitis, the enquiry revealed regular exposure to diesel exhaust fumes in 6 patients (of whom one had also been exposed to ozone and metal oxides), perchloroethylene or trichloroethylene in 3, paint solvents in a further 3. A second series included the next 7 patients with pancreatitis who drank alcohol on a daily basis for several years before their first symptom, but whose attacks continued although they had become, and remained, teetotal: their current occupations involved regular exposure to diesel exhaust fumes in 5 patients, to paint solvents in 1, and to trichloroethylene in 1. The wide variation in the duration of exposure before the first symptom, 2-21 yr, may reflect the net effect on cytochromes P450 of other xenobiotics (e.g. alcohol, cigarettes, caffeine). In several patients, symptoms stopped on removal from exposure to volatile chemicals but recurred on re-exposure. These preliminary findings suggest that occupational exposure to aromatic or chlorinated hydrocarbons may be relevant not only in idiopathic pancreatitis but also in alcohol-related pancreatic disease.
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PMID:Occupational chemicals and pancreatitis: a link? 332 Feb 24

The effect of the natural bile acid, taurolithocholic acid 3-sulfate (TLC-S), on calcium signalling in pancreatic acinar cells has been investigated. TLC-S induced global calcium oscillations and extended calcium transients as well as calcium signals localised to the secretory granule (apical) region of acinar cells. These calcium signals could still be triggered by TLC-S in a calcium-free external solution. TLC-S-induced calcium signals were not inhibited by atropine, but were abolished by caffeine or by depletion of calcium stores, due to prolonged application of ACh. Global calcium signals, produced by TLC-S application, displayed vectorial apical-to-basal polarity. The signals originated in the apical part and were then propagated to the basal region. Other natural bile acids, taurocholate (TC) and taurodeoxycholate (TDC), were also able to produce local and global calcium oscillations (but at higher concentrations than TLC-S). Bile, which can enter pancreas by reflux, has been implicated in the pathology of acute pancreatitis. The calcium releasing properties of bile acids suggest that calcium toxicity could be an important contributing factor in the bile acid-induced cellular damage.
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PMID:Bile acids induce calcium signals in mouse pancreatic acinar cells: implications for bile-induced pancreatic pathology. 1192 68

Ca2+ is a universal intracellular messenger that controls a wide range of cellular processes. In pancreatic acinar cells, acetylcholine and cholecystokinin regulate secretion via generation of repetitive local cytosolic Ca2+ signals in the apical pole. Bile acids and non-oxidative alcohol metabolites can elicit abnormal cytosolic Ca2+ signals that are global and sustained and result in necrosis. Necrosis results from excessive loss of Ca2+ from the endoplasmic reticulum, which is mediated by Ca2+ release through specific channels and inhibition of Ca2+ pumps in intracellular stores, followed by entry of extracellular Ca2+. Reduction of the cellular ATP level has a major role in this process. These abnormal Ca2+ signals, which can be inhibited by caffeine, explain how excessive alcohol intake and biliary disease cause acute pancreatitis, an often-fatal human disease in which the pancreas digests itself and its surroundings.
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PMID:Ca2+ signalling and pancreatitis: effects of alcohol, bile and coffee. 1640 87

Gallstones can cause acute pancreatitis, an often fatal disease in which the pancreas digests itself. This is probably because of biliary reflux into the pancreatic duct and subsequent bile acid action on the acinar cells. Because Ca(2+) toxicity is important for the cellular damage in pancreatitis, we have studied the mechanisms by which the bile acid taurolithocholic acid 3-sulfate (TLC-S) liberates Ca(2+). Using two-photon plasma membrane permeabilization and measurement of [Ca(2+)] inside intracellular stores at the cell base (dominated by ER) and near the apex (dominated by secretory granules), we have characterized the Ca(2+) release pathways. Inhibition of inositol trisphosphate receptors (IP(3)Rs), by caffeine and 2-APB, reduced Ca(2+) release from both the ER and an acidic pool in the granular area. Inhibition of ryanodine receptors (RyRs) by ruthenium red (RR) also reduced TLC-S induced liberation from both stores. Combined inhibition of IP(3)Rs and RyRs abolished Ca(2+) release. RyR activation depends on receptors for nicotinic acid adenine dinucleotide phosphate (NAADP), because inactivation by a high NAADP concentration inhibited release from both stores, whereas a cyclic ADPR-ribose antagonist had no effect. Bile acid-elicited intracellular Ca(2+) liberation from both the ER and the apical acidic stores depends on both RyRs and IP(3)Rs.
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PMID:Bile acids induce Ca2+ release from both the endoplasmic reticulum and acidic intracellular calcium stores through activation of inositol trisphosphate receptors and ryanodine receptors. 1707 64

Bile acids are known to induce Ca(2+) signals in pancreatic acinar cells. We have recently shown that phosphatidylinositol 3-kinase (PI3K) regulates changes in free cytosolic Ca(2+) concentration ([Ca(2+)](i)) elicited by CCK by inhibiting sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA). The present study sought to determine whether PI3K regulates bile acid-induced [Ca(2+)](i) responses. In pancreatic acinar cells, pharmacological inhibition of PI3K with LY-294002 or wortmannin inhibited [Ca(2+)](i) responses to taurolithocholic acid 3-sulfate (TLC-S) and taurochenodeoxycholate (TCDC). Furthermore, genetic deletion of the PI3K gamma-isoform also decreased [Ca(2+)](i) responses to bile acids. Depletion of CCK-sensitive intracellular Ca(2+) pools or application of caffeine inhibited bile acid-induced [Ca(2+)](i) signals, indicating that bile acids release Ca(2+) from agonist-sensitive endoplasmic reticulum (ER) stores via an inositol (1,4,5)-trisphosphate-dependent mechanism. PI3K inhibitors increased the amount of Ca(2+) in intracellular stores during the exposure of acinar cells to bile acids, suggesting that PI3K negatively regulates SERCA-dependent Ca(2+) reloading into the ER. Bile acids inhibited Ca(2+) reloading into ER in permeabilized acinar cells. This effect was augmented by phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)), suggesting that both bile acids and PI3K act synergistically to inhibit SERCA. Furthermore, inhibition of PI3K by LY-294002 completely inhibited trypsinogen activation caused by the bile acid TLC-S. Our results indicate that PI3K and its product, PIP(3), facilitate bile acid-induced [Ca(2+)](i) responses in pancreatic acinar cells through inhibition of SERCA-dependent Ca(2+) reloading into the ER and that bile acid-induced trypsinogen activation is mediated by PI3K. The findings have important implications for the mechanism of acute pancreatitis since [Ca(2+)](i) increases and trypsinogen activation mediate key pathological processes in this disorder.
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PMID:Phosphatidylinositol 3-kinase facilitates bile acid-induced Ca(2+) responses in pancreatic acinar cells. 1715 52

One new bibenzyl (1) and one new phenanthrene (2), together with two known bibenzyls (3-4) and four known diarylheptanoids (5-8) were isolated from the rhizomes of Dioscorea zingiberensis. The structures of 1-2 were elucidated by spectroscopic methods including 1D and 2D NMR. Phenols 1-8 were evaluated for their anti-pancreatitic activities on sodium taurocholate (NaT)-induced pancreatic acinars necrosis. Notably, 0.5mM of compound 6 exhibited comparable inhibitory effect with 5mM of caffeine. Furthermore, compound 6 prevented the ATP depletion and excessive ROS production which could be also involved in mitochondria-mediated injuries in acute pancreatitis. As a result, compound 6 has been demonstrated to be a potential candidate for mediating mitochondrial dysfunction to prevent pancreatic necrosis. This study is also the first report on the isolation of bibenzyls and diarylheptanoids from this plant.
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PMID:Phenolic compounds isolated from Dioscorea zingiberensis protect against pancreatic acinar cells necrosis induced by sodium taurocholate. 2822 64

Pancreatic acinar cells require high rates of amino acid uptake for digestive enzyme synthesis, but excessive concentrations can trigger acute pancreatitis (AP) by mechanisms that are not well understood. We have used three basic natural amino acids L-arginine, L-ornithine, and L-histidine to determine mechanisms of amino acid-induced pancreatic injury and whether these are common to all three amino acids. Caffeine markedly inhibited necrotic cell death pathway activation in isolated pancreatic acinar cells induced by L-arginine, but not L-ornithine, whereas caffeine accelerated L-histidine-induced cell death. Both necroptosis inhibitors of RIPK1 and RIPK3 and a necroptosis activator/apoptosis inhibitor z-VAD increased cell death caused by L-histidine, but not L-arginine or L-ornithine. Cyclophilin D knock-out (Ppif-/-) significantly attenuated cell death induced by L-histidine, but not L-arginine, or L-ornithine. Allosteric modulators of calcium-sensing receptor (CaSR) and G-protein coupled receptor class C group 6 member A (GPRC6A) had inhibitory effects on cell death induced by L-arginine but not L-ornithine or L-histidine. We developed a novel amino acid-induced AP murine model with high doses of L-histidine and confirmed AP severity was significantly reduced in Ppif-/- vs. wild type mice. In L-arginine-induced AP neither Ppif-/-, caffeine, or allosteric modulators of CaSR or GPRC6A reduced pancreatic damage, even though CaSR inhibition with NPS-2143 significantly reduced pancreatic and systemic injury in caerulein-induced AP. These findings demonstrate marked differences in the mechanisms of pancreatic injury induced by different basic amino acids and suggest the lack of effect of treatments on L-arginine-induced AP may be due to conversion to L-ornithine in the urea cycle.
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PMID:Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine. 3069 65