Effect of magnesium supplementation and depletion on the onset and course of acute experimental pancreatitis

Schick, Verena; Scheiber, Jonas A.; Mooren, Frank-Christoph; Turi, Stefan; Ceyhan, Güralp O.; Schnekenburger, Jürgen; Sendler, Matthias; Schwaiger, Theresa; Omercevic, Armin; Brandt, Cindy van den; Fluhr, Gabriele; Domschke, Wolfram; Krüger, Burkhard; Mayerle, Julia; Lerch, Markus M.

doi:10.1136/gutjnl-2012-304274

Cited by 36 publications

(29 citation statements)

References 39 publications

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“…Animals were starved overnight with access to water ad libitum. All animal experiments were performed after prior approval by the institutional animal care committee and as reported previously (56).…”

Section: Methodsmentioning

confidence: 99%

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Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis

Sendler

Maertin

John

et al. 2016

Journal of Biological Chemistry

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Pancreatitis is associated with premature activation of digestive proteases in the pancreas. The lysosomal hydrolase cathepsin B (CTSB) is a known activator of trypsinogen, and its deletion reduces disease severity in experimental pancreatitis. Here we studied the activation mechanism and subcellular compartment in which CTSB regulates protease activation and cellular injury. Cholecystokinin (CCK) increased the activity of CTSB, cathepsin L, trypsin, chymotrypsin, and caspase 3 in vivo and in vitro and induced redistribution of CTSB to a secretory vesicleenriched fraction. Neither CTSB protein nor activity redistributed to the cytosol, where the CTSB inhibitors cystatin-B/C were abundantly present. Deletion of CTSB reduced and deletion of cathepsin L increased intracellular trypsin activation. CTSB deletion also abolished CCK-induced caspase 3 activation, apoptosis-inducing factor, as well as X-linked inhibitor of apoptosis protein degradation, but these depended on trypsinogen activation via CTSB. Raising the vesicular pH, but not trypsin inhibition, reduced CTSB activity. Trypsin inhibition did not affect apoptosis in hepatocytes. Deletion of CTSB affected apoptotic but not necrotic acinar cell death. In summary, CTSB in pancreatitis undergoes activation in a secretory, vesicular, and acidic compartment where it activates trypsinogen. Its deletion or inhibition regulates acinar cell apoptosis but not necrosis in two models of pancreatitis. Caspase 3-mediated apoptosis depends on intravesicular trypsinogen activation induced by CTSB, not CTSB activity directly, and this mechanism is pancreas-specific.Acute pancreatitis has long been regarded as a disease that is characterized by autodigestion of the pancreas by its own proteases (1). This hypothesis appears plausible because no other organ synthesizes and secretes such large amounts of serine and cysteine proteases as the exocrine pancreas (2, 3). However, under physiological conditions, serine proteases are discharged from the pancreas as inactive precursor zymogens, and, most prominently, trypsinogen only undergoes activation when in contact with the intestinal brush border and its enzyme enterokinase. Two discoveries have given new relevance to the autodigestion hypothesis. One is the observation that the autosomal dominant inherited form of pancreatitis is associated with germline mutations in the cationic trypsinogen (PRSS1) gene (4, 5) and that most inherited risk factors for pancreatitis involve alterations in digestive proteases (6, 7). The other is the fact that the mechanism of premature intracellular protease activation and its contributing biochemical and immunological factors are increasingly better understood (8, 9) and have parallels in experimental models that mimic human pancreatitis (10 -12), allowing the conclusion that CTSB 3 is a critical intracellular player. CTSB is a lysosomal hydrolase that has long been shown to activate trypsinogen in vitro (13) but has also been found to be involved in the pathophysiology of experimental models of pa...

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Section: Methodsmentioning

confidence: 99%

“…QIA39 -1EA) was used to analyze acinar cell apoptosis. Quantification of apoptotic cells was performed by ImageJ, and apoptotic cells were calculated as percent of total cells (56).…”

Section: Methodsmentioning

confidence: 99%

Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis

Sendler

Maertin

John

et al. 2016

Journal of Biological Chemistry

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“…Caffeine over consumption ( Figure 5) in the developing world are critical to the induction of caffeine induced magnesium deficiency in myocardial infarction [107,113] and pancreatitis [181][182][183][184]. Caffeine can interfere with thyroid replacement therapy with effects on cardiovascular disease, hypothyroidism and gall bladder disease [185][186].…”

Section: Bacterial Lps and Caffeine Metabolism With Relevance To Naflmentioning

confidence: 99%

Nutrition Therapy Regulates Caffeine Metabolism with Relevance to NAFLD and Induction of Type 3 Diabetes

Martins¹

2017

DMD

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“…GSH derived from homocysteine by the transsulphuration pathway is another absolute requirement for apical exocytosis, not least by protecting participating enzymes in the methionine metabolic route (24) while also sparing critical protein thiols (93). Furthermore, in vitro studies identify the need of CFTR for exocytosis (115), while in vivo experiments show that a surfeit of magnesium stabilizes the exocytosis machinery by antagonizing calcium (132).…”

Section: Methyl / Thiol Insufficiencymentioning

confidence: 99%

Micronutrient ('Antioxidant') Therapy for Chronic Pancreatitis: Basis and Clinical Experience

Braganza

The Pancreapedia: Exocrine Pancreas Knowledge Base

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Effect of magnesium supplementation and depletion on the onset and course of acute experimental pancreatitis

Cited by 36 publications

References 39 publications

Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis

Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis

Nutrition Therapy Regulates Caffeine Metabolism with Relevance to NAFLD and Induction of Type 3 Diabetes

Micronutrient ('Antioxidant') Therapy for Chronic Pancreatitis: Basis and Clinical Experience

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