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)

Hydrogen sulphide (H2S) is a naturally occurring gas synthesized from cysteine. It exhibits vasodilator activity (most probably by opening vascular smooth muscle K(ATP) channels), influences leucocyte chemotaxis and promotes vascular smooth muscle cell apoptosis. Increased biosynthesis of H2S has been demonstrated in animal models of septic/endotoxic and haemorrhagic shock, pancreatitis and carrageenan-evoked hindpaw oedema in the rat. In each case, pharmacological inhibition of H2S biosynthesis is anti-inflammatory.
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PMID:Hydrogen sulphide--a novel mediator of inflammation? 1648 49

Cystic fibrosis (CF) is a recessive genetic disease caused by defects of the cystic fibrosis trans-membrane regulator (CFTR) gene with a median survival of less than 35 years. This work reports on the oldest living German siblings with CF. Besides clinical history, CF genotype and nasal potential difference (NPD) measurement results, the remarkably high exercise activity of the siblings is discussed as a disease-modifying factor. Both male patients have an overall mild pulmonary manifestation. They have suffered from abdominal symptoms since their early childhood, including recurrent pancreatitis and diffuse symptoms leading to partial gastric resection. They were diagnosed as having CF with positive sweat tests at the advanced ages of 45 and 43 years, respectively. Later on genotyping revealed compound heterozygosity for F508del and 2789+5G-->A. Using NPD we demonstrated a CF-typical inhibition of the NPD by the Na channel blocker amiloride, although in both siblings the remaining CFTR function and alternate chloride channel function were detected during superfusion of the nasal epithelium with isoproterenol and ATP. Long-term survival with CF is basically influenced by the CFTR genotype. The patients' genotype was discussed as a mild one with remaining CFTR function. We demonstrated this residual CFTR function in both siblings using NPD. Additionally the siblings' continuous healthy lifestyle and their engagement in a remarkably high level of exercise activities from early childhood to the present possibly have an important effect on the long-term outcome of CF as disease-modifying factors. In this regard this report can encourage CF patients to maintain a high level of physical activity in their daily lives.
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PMID:Cystic fibrosis in 65- and 67-year-old siblings. Clinical feature and nasal potential difference measurement in patients with genotypes F508del and 2789+5G-->A. 1676 70

Normal physiological regulation depends on Ca(2+) microdomains, because there is a need to spatially separate Ca(2+) regulation of different cellular processes. It is only possible to generate local Ca(2+) signals transiently; so, there is an important functional link between Ca(2+) spiking and microdomains. The pancreatic acinar cell provides a useful cell biological model, because of its clear structural and functional polarization. Although local Ca(2+) spiking in the apical (granular) microdomain regulates fluid and enzyme secretion, prolonged global elevations of the cytosolic Ca(2+) concentration are associated with the human disease acute pancreatitis, in which proteases in the granular region become inappropriately activated and digest the pancreas and its surroundings. A major cause of pancreatitis is alcohol abuse and it has now been established that fatty acid ethyl esters and fatty acids, non-oxidative alcohol metabolites, are principally responsible for causing the acinar cell damage. The fatty acid ethyl esters release Ca(2+) from the endoplasmic reticulum and the fatty acids inhibit markedly mitochondrial ATP generation, which prevents the acinar cell from disposing of the excess Ca(2+) in the cytosol. Because of the abolition of ATP-dependent Ca(2+) pump activity, all intracellular Ca(2+) concentration gradients disappear and the most important part of the normal regulatory machinery is thereby destroyed. The end stage is necrosis.
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PMID:Failure of calcium microdomain generation and pathological consequences. 1704 97

Black foot disease (BFD) is a peripheral arterial occlusive disease found among the inhabitants of the southwest coast of Taiwan. Moreover, within the BFD-endemic areas, diabetes mellitus occur at significantly higher rates than in other areas of Taiwan. A high concentration of humic acid (HA), and arsenic (As) are present in the artesian well water from BFD-endemic area. The aim of this paper is to study the diabetogenic effect of the combination of HA and AS. Treatment of HIT-T15 cells with HA, As, or both of them resulted loss of cell viability, apoptosis, depletion of ATP, increment of oxidative stress, activation of caspase 3, and dysfunction of insulin secretion. In addition, the plasma insulin of ICR mice, which were exposed to HA and As in drinking water for 12 weeks, was decreased in the 5, 7, and 12 weeks, and increased at early stage of exposure (3 weeks). The results reported herein reveal that HA and As exert HIT-T15 cell dysfunction and inhibited insulin secretive effects. In addition, the sub-acute peri-pancreatitis and islet damage caused by the infiltration of inflammatory cells after exposure of HA and As in drinking water for 5 weeks. Our study has important implications in the diabetogenic effect of the HA and AS which may be mediated by ROS and further information of the toxicity mechanisms will provide under our progressive studies.
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PMID:The diabetogenic effects of the combination of humic acid and arsenic: in vitro and in vivo studies. 1762 97

Pancreatitis is a severe and frequently lethal disorder, a major cause of which is alcohol abuse. Parenchymal cell death is a major complication of pancreatitis. In experimental models of acute pancreatitis, acinar cells have been shown to die through both necrosis and apoptosis, the two principal pathways of cell death. The severity of experimental acute pancreatitis correlates directly with the extent of necrosis and inversely with apoptosis. Thus, understanding the regulation of apoptosis and necrosis is becoming exceedingly important in investigations of the pathogenesis and treatment of pancreatitis. Over the past decade, the mitochondria have emerged as a master regulator of cell death in various physiological and pathological processes. Release of mitochondrial cytochrome c into the cytosol is a central event in apoptosis, whereas mitochondrial depolarization resulting in ATP depletion leads to necrosis. The present review focuses on the mitochondrial mechanisms of death responses in pancreatitis, with emphasis on mitochondrial membrane permeabilization and its role in the balance between apoptosis and necrosis in acute pancreatitis, and alcohol's effects on death responses of pancreatitis.
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PMID:Mitochondrial mechanisms of death responses in pancreatitis. 1833 59

Impairment of the normal spatiotemporal pattern of intracellular Ca(2+) ([Ca(2+)](i)) signaling, and in particular, the transition to an irreversible "Ca(2+) overload" response, has been implicated in various pathophysiological states. In some diseases, including pancreatitis, oxidative stress has been suggested to mediate this Ca(2+) overload and the associated cell injury. We have previously demonstrated that oxidative stress with hydrogen peroxide (H(2)O(2)) evokes a Ca(2+) overload response and inhibition of plasma membrane Ca(2+)-ATPase (PMCA) in rat pancreatic acinar cells (Bruce JI and Elliott AC. Am J Physiol Cell Physiol 293: C938-C950, 2007). The aim of the present study was to further examine this oxidant-impaired inhibition of the PMCA, focusing on the role of the mitochondria. Using a [Ca(2+)](i) clearance assay in which mitochondrial Ca(2+) uptake was blocked with Ru-360, H(2)O(2) (50 microM-1 mM) markedly inhibited the PMCA activity. This H(2)O(2)-induced inhibition of the PMCA correlated with mitochondrial depolarization (assessed using tetramethylrhodamine methylester fluorescence) but could occur without significant ATP depletion (assessed using Magnesium Green fluorescence). The H(2)O(2)-induced PMCA inhibition was sensitive to the mitochondrial permeability transition pore (mPTP) inhibitors, cyclosporin-A and bongkrekic acid. These data suggest that oxidant-induced opening of the mPTP and mitochondrial depolarization may lead to an inhibition of the PMCA that is independent of mitochondrial Ca(2+) handling and ATP depletion, and we speculate that this may involve the release of a mitochondrial factor. Such a phenomenon may be responsible for the Ca(2+) overload response, and for the transition between apoptotic and necrotic cell death thought to be important in many disease states.
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PMID:Oxidant-induced inhibition of the plasma membrane Ca2+-ATPase in pancreatic acinar cells: role of the mitochondria. 1878 78

Pancreatitis, a potentially fatal disease in which the pancreas digests itself as well as its surroundings, is a well recognized complication of hyperlipidemia. Fatty acids have toxic effects on pancreatic acinar cells and these are mediated by large sustained elevations of the cytosolic Ca(2+) concentration. An important component of the effect of fatty acids is due to inhibition of mitochondrial function and subsequent ATP depletion, which reduces the operation of Ca(2+)-activated ATPases in both the endoplasmic reticulum and the plasma membrane. One of the main causes of pancreatitis is alcohol abuse. Whereas the effects of even high alcohol concentrations on isolated pancreatic acinar cells are variable and often small, fatty acid ethyl esters--synthesized by combination of alcohol and fatty acids--consistently evoke major Ca(2+) release from intracellular stores, subsequently opening Ca(2+) entry channels in the plasma membrane. The crucial trigger for pancreatic autodigestion is intracellular trypsin activation. Although there is still uncertainty about the exact molecular mechanism by which this Ca(2+)-dependent process occurs, progress has been made in identifying a subcellular compartment--namely acid post-exocytotic endocytic vacuoles--in which this activation takes place.
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PMID:Fatty acids, alcohol and fatty acid ethyl esters: toxic Ca2+ signal generation and pancreatitis. 1932 25

Acinar cells in pancreatitis die through apoptosis and necrosis, the roles of which are different. The severity of experimental pancreatitis correlates directly with the extent of necrosis and inversely, with apoptosis. Apoptosis is mediated by the release of cytochrome c into the cytosol followed by caspase activation, whereas necrosis is associated with the mitochondrial membrane potential (DeltaPsim) loss leading to ATP depletion. Here, we investigate the role of Bcl-2 proteins in apoptosis and necrosis in pancreatitis. We found up-regulation of prosurvival Bcl-2 proteins in pancreas in various experimental models of acute pancreatitis, most pronounced for Bcl-xL. This up-regulation translated into increased levels of Bcl-xL and Bcl-2 in pancreatic mitochondria. Bcl-xL/Bcl-2 inhibitors induced DeltaPsim loss and cytochrome c release in isolated mitochondria. Corroborating the results on mitochondria, Bcl-xL/Bcl-2 inhibitors induced DeltaPsim loss, ATP depletion and necrosis in pancreatic acinar cells, both untreated and hyperstimulated with CCK-8 (in vitro pancreatitis model). Together Bcl-xL/Bcl-2 inhibitors and CCK induced more necrosis than either treatment alone. Bcl-xL/Bcl-2 inhibitors also stimulated cytochrome c release in acinar cells leading to caspase-3 activation and apoptosis. However, different from their effect on pronecrotic signals, the stimulation by Bcl-xL/Bcl-2 inhibitors of apoptotic responses was less in CCK-treated than control cells. Therefore, Bcl-xL/Bcl-2 inhibitors potentiated CCK-induced necrosis but not apoptosis. Correspondingly, transfection with Bcl-xL siRNA stimulated necrosis but not apoptosis in the in vitro pancreatitis model. Further, in animal models of pancreatitis Bcl-xL up-regulation inversely correlated with necrosis, but not apoptosis. Results indicate that Bcl-xL and Bcl-2 protect acinar cells from necrosis in pancreatitis by stabilizing mitochondria against death signals. We conclude that Bcl-xL/Bcl-2 inhibition would aggravate acute pancreatitis, whereas Bcl-xL/Bcl-2 up-regulation presents a strategy to prevent or attenuate necrosis in pancreatitis.
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PMID:Prosurvival Bcl-2 proteins stabilize pancreatic mitochondria and protect against necrosis in experimental pancreatitis. 1933 32

In contrast to apoptosis, necrosis is generally viewed as a pro-inflammatory cell death mechanism. Accumulation of autophagosomes and massive acinar cell necrosis is observed in human acute pancreatitis, a severe and potentially lethal inflammatory condition. We have investigated the incidence of apoptosis, autophagy and necrosis affecting acinar cells in a rat model of acute pancreatitis induced by chronic alcohol intake and acute endotoxemia. We have observed that the combination of alcohol exposure and endotoxemia results in substantial accumulation of autophagosomes without an increase in autolysosomes, coupled to the depletion of LAMP-2, a lysosomal protein required for the proper fusion of autophagosomes with lysosomes. Alcohol plus endotoxemia favors the switch from apoptotic to necrotic cell death, as indicated by histopathological examination, reduced ATP levels, suppressed caspase activation, as well as the nuclear release of the proinflammatory factor HMGB1. Importantly, patients with alcoholic pancreatitis also exhibit local LAMP-2 depletion, recapitulating the results obtained in the animal model. We suggest that acinar cell vacuolization in pancreatitis is mediated by an endotoxemia-induced depletion of LAMP-2, which in turn facilitates the accumulation of autophagosomes due to the deficient formation of autolysosomes. Hence, we postulate that the depletion of lysosomal proteins may play a critical role in the pathogenesis of acute pancreatitis.
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PMID:Impaired autophagosome-lysosome fusion in the pathogenesis of pancreatitis. 1945 81

Chemokines have been known to play a critical role in pathogenesis of chronic pancreatitis and acinar cell death. However, the role played by one of the CXC chemokines: CXCL10 in regulation of acinar cell death has remained unexplored. Hence, this study was designed to assess the role of CXCL10 promoting apoptosis in ex vivo cultured acinar cells. Primary human pancreatic acinar cell cultures were established and exposed to varying doses of CXCL10 for different time intervals. Apoptotic induction was evaluated by both qualitative as well as quantitative analyses. Various mediators of apoptosis were also studied by Western blotting, membrane potential (Psim) and ATP depletion in acinar cells. Analysis of apoptosis via DNA ladder and cell death detection - ELISA demonstrated that CXCL10 induced 3.9-fold apoptosis when administrated at an optimal dose of 0.1 mug of recombinant CXCL10 for 8 h. Quantitative analysis using FACS and dual staining by PI-annexin showed increased apoptosis (48.98 and 53.78% respectively). The involvement of upstream apoptotic regulators like pJNK, p38 and Bax was established on the basis of their increased expression of CXCL10. The change of Psim by 50% was observed in the presence of CXCL10 in treated acinar cells along with enhanced expression of Cytochrome C, apaf-1 and caspase 9/3 activation. In addition, ATP depletion was also noticed in CXCL10 stimulated acinar cells. CXCL10 induces cell death in human cultured pancreatic cells leading to apoptosis and DNA fragmentation via CXCR3 signalling. These signalling mechanisms may play an important role in parenchymal cell loss and injury in pancreatitis.
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PMID:Potential role of CXCL10 in the induction of cell injury and mitochondrial dysfunction. 2004 63


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