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Victor Sanchezmargalet – One of the best experts on this subject based on the ideXlab platform.

  • reprint of metabolic effects and mechanism of action of the chromogranin a derived peptide Pancreastatin
    Regulatory Peptides, 2010
    Co-Authors: Victor Sanchezmargalet, Carmen Gonzalezyanes, Souad Najib, Jose Santosalvarez
    Abstract:

    Abstract Pancreastatin is one of the regulatory peptides derived from intracellular and/or extracellular processing of chromogranin A, the soluble acidic protein present in the secretory granules of the neuroendocrine system. While the intracellular functions of chromogranin A include formation and maturation of the secretory granule, the major extracellular functions are generation of biologically active peptides with demonstrated autocrine, paracrine or endocrine activities. In this review, we will focus on the metabolic function of one of these peptides, Pancreastatin, and the mechanisms underlying its effects. Many different reported effects have implicated PST in the modulation of energy metametabolism, with a general counterregulatory effect to that of insulin. Pancreastatin induces glycogenolysis in liver and lipolysis in adipocytes. Metabolic effects have been confirmed in humans. Moreover, naturally occurring human variants have been found, one of which (Gly297Ser) occurs in the functionally important carboxy-terminus of the peptide, and substantially increases the peptide‘s potency to inhibit cellular glucose uptake. Thus, qualitative hereditary alterations in Pancreastatin‘s primary structure may give rise to interindividual differences in glucose and lipid metabolism. Pancreastatin activates a receptor signaling system that belongs to the seven-spanning transmembrane receptor coupled to a Gq–PLCβ–calcium–PKC signaling pathway. Increased Pancreastatin plasma levels, correlating with catecholamines levels, have been found in insulin resistance states, such as gestational diabetes or essential hypertension. Pancreastatin plays important physiological role in potentiating the metabolic effects of catecholamines, and may also play a pathophysiological role in insulin resistance states with increased sympathetic activity.

  • metabolic effects and mechanism of action of the chromogranin a derived peptide Pancreastatin
    Regulatory Peptides, 2010
    Co-Authors: Victor Sanchezmargalet, Carmen Gonzalezyanes, Souad Najib, Jose Santosalvarez
    Abstract:

    Abstract Pancreastatin is one of the regulatory peptides derived from intracellular and/or extracellular processing of chromogranin A, the soluble acidic protein present in the secretory granules of the neuroendocrine system. While the intracellular functions of chromogranin A include formation and maturation of the secretory granule, the major extracellular functions are generation of biologically active peptides with demonstrated autocrine, paracrine or endocrine activities. In this review, we will focus on the metabolic function of one of these peptides, Pancreastatin, and the mechanisms underlying its effects. Many different reported effects have implicated PST in the modulation of energy metametabolism, with a general counterregulatory effect to that of insulin. Pancreastatin induces glycogenolysis in liver and lipolysis in adipocytes. Metabolic effects have been confirmed in humans. Moreover, naturally occurring human variants have been found, one of which (Gly297Ser) occurs in the functionally important carboxy-terminus of the peptide, and substantially increases the peptide‘s potency to inhibit cellular glucose uptake. Thus, qualitative hereditary alterations in Pancreastatin‘s primary structure may give rise to interindividual differences in glucose and lipid metabolism. Pancreastatin activates a receptor signaling system that belongs to the seven-spanning transmembrane receptor coupled to a Gq–PLCβ–calcium–PKC signaling pathway. Increased Pancreastatin plasma levels, correlating with catecholamines levels, have been found in insulin resistance states, such as gestational diabetes or essential hypertension. Pancreastatin plays important physiological role in potentiating the metabolic effects of catecholamines, and may also play a pathophysiological role in insulin resistance states with increased sympathetic activity.

  • Pancreastatin a chromogranin a derived peptide inhibits dna and protein synthesis by producing nitric oxide in htc rat hepatoma cells
    Journal of Hepatology, 2001
    Co-Authors: Victor Sanchezmargalet, Carmen Gonzalezyanes, Souad Najib
    Abstract:

    Abstract Background/Aims : Pancreastatin, a chromogranin A-derived peptide, has a counter-regulatory effect on insulin action. We have previously characterized Pancreastatin receptor and signalling in rat liver and HTC hepatoma cells. A G α q/11 -PLC- β pathway leads to an increase in [Ca 2+ ] i , PKC and mitogen activated protein kinase (MAPK) activation. These data suggested that Pancreastatin might have a role in growth and proliferation, similar to other calcium-mobilizing hormones. Methods : DNA and protein synthesis were measured as [ 3 H]-thymidine and [ 3 H]-leucine incorporation. Nitric oxide (NO) was determined by the Griess method and cGMP production was quantified by enzyme-linked immunoassay. Results : Contrary to the expected results, we have found that Pancreastatin inhibits protein and DNA synthesis in HTC hepatoma cells. On the other hand, when the activity of NO synthase was inhibited by N -monomethyl- l –arginine (NMLA), the inhibitory effect of Pancreastatin on DNA and protein synthesis was not only reverted, but a dose-dependent stimulatory effect was observed, probably due to MAPK activation, since it was prevented by PD98059. These data strongly suggested the role of NO in the inhibitory effect of Pancreastatin on protein and DNA synthesis, which is overcoming the effect on MAPK activation. Moreover, Pancreastatin dose-dependently increased NO production in parallel to cyclic guanosine monophosphate (cGMP). Both effects were prevented by NMLA. Finally, an indirect effect of Pancreastatin through the induction of apoptosis was ruled out. Conclusions : Therefore, the NO and the cGMP produced by the NO-activated guanylate cyclase may mediate the dose-dependent inhibitory effect of Pancreastatin on growth and proliferation in HTC hepatoma cells.

R Goberna – One of the best experts on this subject based on the ideXlab platform.

  • increased plasma Pancreastatin like levels in gestational diabetes correlation with catecholamine levels
    Diabetes Care, 1998
    Co-Authors: Victor Sanchezmargalet, J A Lobon, Fernando Escobarjimenez, Amalia Gonzalez, M L Fernandezsoto, R Goberna
    Abstract:

    OBJECTIVE: To investigate plasma Pancreastatin (a chromogranin A-derived peptide) and catecholamine levels (counterregulatory hormones) in subjects with gestational diabetes compared with normal pregnant subjects. RESEARCH DESIGN AND METHODS: Fasting blood samples were obtained from 11 normal pregnant and 12 nonobese gestational diabetic subjects at late pregnancy (30+/-1 weeks). Selection criteria were those recommended by the National Diabetes Data Group (modified from O’Sullivan original criteria). Plasma glucose, insulin, glucagon, Pancreastatin-like, epinephrine, and norepinephrine were measured. RESULTS: Gestational diabetic subjects had significantly higher insulin levels than control pregnant subjects (18+/-1 vs. 15+/-1 microU/ml), whereas glucose and glucagon levels where comparable in the two groups. However, increased catecholamine levels (epinephrine and norepinephrine) were found in the gestational diabetic group. We also found increased Pancreastatin-like levels in these patients compared with the pregnant control group (46+/-2 vs. 30+/-2 pmol/l). Actually, Pancreastatin levels positively correlated with both epinephrine (r = 0.34) and norepinephrine (r = 0.80) levels. CONCLUSIONS: Catecholamine and Pancreastatin-like levels were found elevated in gestational diabetic subjects. These counterregulatory hormones may play a role in the insulin resistance syndrome of gestational diabetes.

  • Pancreastatin further evidence for its consideration as a regulatory peptide
    Journal of Molecular Endocrinology, 1996
    Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R Goberna
    Abstract:

    : Pancreastatin is a 49 amino acid peptide first isolated, purified and characterized from the porcine pancreas, and whose biological activity in different tissues can be assigned to the C-terminal part of the molecule. Pancreastatin has a prohormonal precursor, chromogranin A (CGA), which is a glycoprotein present in neuroendocrine cells, including the endocrine pancreas. Both intracellular and extracellular processing of CGA can yield Pancreastatin. This processing is tissue-specific, with the pancreatic islet and antral gastric endocrine cells being the major source of fully processed Pancreastatin. Most of the circulating CGA is secreted by chromaffin tissue. Therefore, peripheral processing of CGA is probably the major indirect source of Pancreastatin. Pancreastatin seems to have a general modulatory control on endocrine (insulin, glucagon, parathormone) and exocrine (pancreatic, gastric) secretion from tissues close to the source of production. This has led to the assumption that Pancreastatin may be a peptide with an autocrine and paracrine function. It has recently been revealed to be a peptide with a metabolic function counter-regulatory to insulin action. This effect, in conjunction with the inhibitory effect on insulin and pancreatic exocrine secretion, points to a role in the physiology of stress. The molecular mechanism of the glycogenolytic effect of Pancreastatin is better known, although further work is still needed. In general, more studies should be carried out at the molecular level to investigate the mechanism of action of Pancreastatin and thus to clarify its physiological role in the neuroendocrine system.

  • Pancreastatin action in the liver dual coupling to different g proteins
    Cellular Signalling, 1996
    Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R Goberna
    Abstract:

    Abstract Pancreastatin is a 49 amino acid peptide first isolated, purified and characterized from porcine pancreas. Its biological activity in different tissues can be assigned to the C-terminal part of the molecule. Pancreastatin has a prohormonal precursor, chromogranin A, which is a glycoprotein present in neuroendocrine cells, including the endocrine pancreas. We have been interested in Pancreastatin action in the liver. We found that Pancreastatin has a glycogenolytic effect in the hepatocyte both in vivo and in vitro. We then studied and characterized the specific Pancreastatin receptor in the rat liver plasma membrane, as well as the specific signal transduction. This receptor appears to be coupled to two different G protproteins. A pertussis toxin-insensitive G protproteins leads to the activation of phospholipase C, and therefore mediates the glycogenolytic effect in the liver by increasing cytoplasmic free calcium and stimulating protein kinase C. The role of cyclic GMP in the action of Pancreastatin is not known yet, although it seems to regulate negatively the activation of phospholipase C. The precise mechanism by which Pancreastatin stimulates quanylate cyclase activity remains to be studied.

J E S Ardill – One of the best experts on this subject based on the ideXlab platform.

  • A rapid rise in circulating Pancreastatin in response to somatostatin analogue therapy is associated with poor survival in patients with neuroendocrine tumours.
    Annals of clinical biochemistry, 2008
    Co-Authors: R L Stronge, G B Turner, B T Johnston, D R Mccance, A Mcginty, C C Patterson, J E S Ardill
    Abstract:

    To assess the value of Pancreastatin as a predictive factor for identifying patients with neuroendocrine tumours (NETs) who respond poorly to somatostatin analogues. A retrospective study of patients with NETs. Patient records from the Northern Ireland Neuroendocrine Tumour Register were interrogated. Those who had Pancreastatin concentrations measured on two or more occasions, before and during somatostatin analogue therapy (within the set time-limits) were selected. Data relating to diagnosis, surgery, somatostatin analogue therapy and survival outcome were noted. Data were subjected to univariate and multivariate analysis using Cox proportional hazard model. Fifty-nine patients with gastroenteropancreatic NETs fulfilled the inclusion criteria. Factors associated with a poor survival outcome on univariate analysis were primary tumour site (P = 0.006) and rapid rise in Pancreastatin during somatostatin analogue treatment (P < 0.001). In multivariate analysis, highly significant clinical prognostic indicators were: tumour location (P < 0.001), pre-treatment Pancreastatin (P < 0.001) and Pancreastatin change (P < 0.001). This study endorses the finding that Pancreastatin is a useful prognostic indicator of neuroendocrine disease. On commencement of treatment, one-third of the subjects showed an immediate negative Pancreastatin response to somatostatin analogues, which was associated with poor survival. This is the first study to document such an association. These findings have significant therapeutic consequences. In the presence of a rapidly rising Pancreastatin alternative, treatment modalities should be sought.

  • a rapid rise in circulating Pancreastatin in response to somatostatin analogue therapy is associated with poor survival in patients with neuroendocrine tumours
    Annals of Clinical Biochemistry, 2008
    Co-Authors: R L Stronge, G B Turner, B T Johnston, D R Mccance, A Mcginty, Christopher Patterson, J E S Ardill
    Abstract:

    AimTo assess the value of Pancreastatin as a predictive factor for identifying patients with neuroendocrine tumours (NETs) who respond poorly to somatostatin analogues.MethodsA retrospective study of patients with NETs. Patient records from the Northern Ireland Neuroendocrine Tumour Register were interrogated. Those who had Pancreastatin concentrations measured on two or more occasions, before and during somatostatin analogue therapy (within the set time-limits) were selected. Data relating to diagnosis, surgery, somatostatin analogue therapy and survival outcome were noted. Data were subjected to univariate and multivariate analysis using Cox proportional hazard model.ResultsFifty-nine patients with gastroenteropancreatic NETs fulfilled the inclusion criteria. Factors associated with a poor survival outcome on univariate analysis were primary tumour site (P = 0.006) and rapid rise in Pancreastatin during somatostatin analogue treatment (P < 0.001). In multivariate analysis, highly significant clinical pr…

Miguel Lucas – One of the best experts on this subject based on the ideXlab platform.

  • Pancreastatin further evidence for its consideration as a regulatory peptide
    Journal of Molecular Endocrinology, 1996
    Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R Goberna
    Abstract:

    : Pancreastatin is a 49 amino acid peptide first isolated, purified and characterized from the porcine pancreas, and whose biological activity in different tissues can be assigned to the C-terminal part of the molecule. Pancreastatin has a prohormonal precursor, chromogranin A (CGA), which is a glycoprotein present in neuroendocrine cells, including the endocrine pancreas. Both intracellular and extracellular processing of CGA can yield Pancreastatin. This processing is tissue-specific, with the pancreatic islet and antral gastric endocrine cells being the major source of fully processed Pancreastatin. Most of the circulating CGA is secreted by chromaffin tissue. Therefore, peripheral processing of CGA is probably the major indirect source of Pancreastatin. Pancreastatin seems to have a general modulatory control on endocrine (insulin, glucagon, parathormone) and exocrine (pancreatic, gastric) secretion from tissues close to the source of production. This has led to the assumption that Pancreastatin may be a peptide with an autocrine and paracrine function. It has recently been revealed to be a peptide with a metabolic function counter-regulatory to insulin action. This effect, in conjunction with the inhibitory effect on insulin and pancreatic exocrine secretion, points to a role in the physiology of stress. The molecular mechanism of the glycogenolytic effect of Pancreastatin is better known, although further work is still needed. In general, more studies should be carried out at the molecular level to investigate the mechanism of action of Pancreastatin and thus to clarify its physiological role in the neuroendocrine system.

  • Pancreastatin action in the liver dual coupling to different g proteins
    Cellular Signalling, 1996
    Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R Goberna
    Abstract:

    Abstract Pancreastatin is a 49 amino acid peptide first isolated, purified and characterized from porcine pancreas. Its biological activity in different tissues can be assigned to the C-terminal part of the molecule. Pancreastatin has a prohormonal precursor, chromogranin A, which is a glycoprotein present in neuroendocrine cells, including the endocrine pancreas. We have been interested in Pancreastatin action in the liver. We found that Pancreastatin has a glycogenolytic effect in the hepatocyte both in vivo and in vitro. We then studied and characterized the specific Pancreastatin receptor in the rat liver plasma membrane, as well as the specific signal transduction. This receptor appears to be coupled to two different G proteins. A pertussis toxin-insensitive G proteins leads to the activation of phospholipase C, and therefore mediates the glycogenolytic effect in the liver by increasing cytoplasmic free calcium and stimulating protein kinase C. The role of cyclic GMP in the action of Pancreastatin is not known yet, although it seems to regulate negatively the activation of phospholipase C. The precise mechanism by which Pancreastatin stimulates quanylate cyclase activity remains to be studied.

  • Pancreastatin activates protein kinase c by stimulating the formation of 1 2 diacylglycerol in rat hepatocytes
    Biochemical Journal, 1994
    Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R Goberna
    Abstract:

    We describe here the stimulation by Pancreastatin of 1,2-diacylglycerol production and protein kinase C activity in liver plasma membrane and isolated hepatocytes. The dose-dependency for the stimulation of both processes was similar to the recently described pattern of glucose output and cytosolic Ca2+ transients produced by Pancreastatin. The time course of diacylglycerol production at 30 degrees C showed a rapid increase within 5 min, reaching a maximum at 10 min. Protein kinase C from hepatocytes was dependent on Ca2+ and phosphatidylserine. Neither the Pancreastatin-stimulated diacylglycerol production nor the activation of protein kinase C was affected by pretreatment with pertussis toxin. However, the presence of GTP partially inhibited this Pancreastatin stimulation of 1,2-diacylglycerol in a dose-dependent manner, although GTP alone stimulates diacylglycerol accumulation. This inhibitory effect of GTP on Pancreastatin stimulation of diacylglycerol synthesis was completely abolished by the pretreatment with pertussis toxin. In conclusion, this study provides evidence that Pancreastatin stimulates the formation of 1,2-diacylglycerol by a pertussis-toxin-independent mechanism, which may be responsible for the Pancreastatin activation of protein kinase C.

R Hakanson – One of the best experts on this subject based on the ideXlab platform.

  • histamine depletion does not affect Pancreastatin secretion from isolated rat stomach ecl cells
    European Journal of Pharmacology, 2000
    Co-Authors: Erik Lindstrom, Per Norlen, R Hakanson
    Abstract:

    Abstract ECL cells co-secrete histamine and Pancreastatin, a chromogranin A-derived peptide, in response to gastrin. The aim of the study was to explore possible ways to deplete ECL cells of histamine without affecting Pancreastatin and to examine how histamine depletion affects Pancreastatin secretion. Isolated rat stomach ECL cells (80–85% purity), prepared by counter-flow elutriation, were cultured for 48 h in the presence of α-fluoromethylhistidine (histidine decarboxylase inhibitor), bafilomycin A 1 (inhibitor of vacuolar-type proton-translocating ATPase) or reserpine (inhibitor of vesicular monoamine transporter). At this stage, the cells were challenged with 10 nM (EC 100 ) gastrin-17 for 30 min. Histamine and Pancreastatin were determined by radioimmunoassay. Maximally effective concentrations of α-fluoromethylhistidine, bafilomycin A 1 and reserpine were found to lower ECL-cell histamine (by 60%, 78% and 80%, respectively) without affecting Pancreastatin. Basal histamine secretion was reduced in a dose-dependent manner by all three drugs. Gastrin-evoked histamine secretion was reduced greatly by the three agents, while Pancreastatin secretion was unaffected. The results show that histamine can be depleted not only by inhibiting its formation (α-fluoromethylhistidine), but also (and more effectively) by inhibiting histamine vesicular uptake, directly (reserpine) or indirectly (bafilomycin A 1 ). The results also indicate that although histamine is co-stored with Pancreastatin, it is not required for either storage or secretion of Pancreastatin.

  • expression of the chromogranin a derived peptides Pancreastatin and we14 in rat stomach ecl cells
    Regulatory Peptides, 1997
    Co-Authors: Per Norlen, Duan Chen, Chunmei Zhao, W J Curry, C F Johnston, R Hakanson
    Abstract:

    Abstract The ECL cells constitute the predominant endocrine cell population in the mucosa of the acid-secreting part of the stomach (fundus). They are rich in chromogranin A (CGA), histamine and histidine decarboxylase (HDC). They secrete CGA-derived peptides and histamine in response to gastrin. The objective of this investigation was to examine the expression of Pancreastatin (rat CGA 266-314 ) and WE 14 (rat CGA 343-356 ) in rat stomach ECL cells. The distribution and cellular localisation of Pancreastatin– and WE 14 -like immunoreactivities (LI) were analysed by radioimmunoassay and immunohistochemistry with antibodies against Pancreastatin, WE 14 and HDC. The effect of food deprivation on circulating Pancreastatin-LI was examined in intact rats and after gastrectomy or fundectomy. Rats received gastrin-17 (5 nmol/kg/h) by continuous intravenous infusion or omeprazole (400 μmol/kg) once daily by the oral route, to induce hypergastrinemia. CGA-derived peptides in the ECL cells were characterised by gel permpermeationochromatography. The expression of CGA mRNA was examined by Northern blot analysis. Among all of the endocrine cells in the body, the ECL cell population was the richest in Pancreastatin-LI, containing 20–25% of the total body content. Food deprivation and/or surgical removal of the ECL cells lowered the level of Pancreastatin-LI in serum by about 80%. Activation of the ECL cells by gastrin infusion or omeprazole treatment raised the serum level of Pancreastatin-LI, lowered the concentrations of Pancreastatin– and WE 14 -LI in the ECL cells and increased the CGA mRNA concentration. Chromatographic analysis of the various CGA immunoreactive components in the ECL cells of normal and hypergastrinemic rats suggested that these cells respond to gastrin with a preferential release of the low-molecular-mass forms.

  • evidence that rat stomach ecl cells represent the main source of circulating Pancreastatin
    Regulatory Peptides, 1997
    Co-Authors: Keizo Kimura, Duan Chen, Erik Lindstrom, Chunmei Zhao, R Hakanson
    Abstract:

    Abstract Recently, we showed that the ECL cells in the oxyntic mucosa of the rat stomach are an important source of circulating Pancreastatin, a fragment of chromogranin A. The present study examined how much the ECL cells contribute to the circulating levels of Pancreastatin during omeprazole-evoked hypergastrinemia. Rats received omeprazole (400 μmol kg−1 day−1) by the oral route for 3 weeks. Two weeks after the start of the treatment, the rats were subjected to a sham operation or fundectomy. The concentrations of gastrin and Pancreastatin in serum were monitored before and after the operations. The ECL cells were visualized by Pancreastatin immunostaining and their number was determined. The activity of oxyntic mucosal histidine decarboxylase (HDC) was measured before and after 2 weeks of omeprazole treatment. Omeprazole-induced hypergastrinemia resulted in elevated serum Pancreastatin and increased oxyntic mucosal HDC activity. Pancreastatin-immunoreactive cells were equally numerous before and after 2 weeks of omeprazole treatment. After surgical removal of the ECL cells by fundectomy, the serum gastrin concentration remained high whereas the serum Pancreastatin concentration decreased by 90%. We conclude that the ECL cells in omeprazole-treated rats are responsible for 90% of circulating Pancreastatin.