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1

Leptin is the modulator of HSP60 gene expression in AR42J cells

100%

Bonior J., Jaworek J., Konturek S. J., Pawlik W. W.

Journal of Physiology and Pharmacology. Supplement

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2006

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tom 57

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nr 7

135-143

Leptin, circulating protein involved in the control of body weight and energy expenditure received attention as a modulator of immune response of the organism. Leptin receptors have been detected in the pancreas and experimental studies have shown that leptin protects the pancreas against the damage induced by caerulein overstimulation. Heat shock proteins (HSP) are endogenous proteins produced by various cells exposed to high temperature or to the noxious agents. HSP protect the cells against various environmental and endogenous stressors. The implication of HSP60 in the leptin-induced pancreatic protection has not been examined yet. The aim of this study was: to investigate the changes of HSP60 mRNA signal in the pancreatic AR42J cells subjected to caerulein and leptin. AR42J cells were incubated in standart medium at 37°C for: 0, 1, 3, 5, 12 or 24 h, under basal conditions. Incubation time of 3 h was selected for the next experiments. AR42J cells were incubated in presence of caerulein (10-11, 10-9 or 10-7M), leptin (10-8 or 10-6M), or combination of above. Gene expression for HSP60 was determined by RT-PCR. The mRNA signal for HSP60 has been observed in AR42J pancreatic cells under basal conditions. Incubation of AR42J cells in presence of leptin (10-8 or 10-6M) resulted in the significant increase of gene expression for HSP60 in both groups of AR42J cells. Caerulein stimulation reduced mRNA signal for HSP60. The strongest mRNA signal for HSP60 has been observed after the exposition of AR42J cells to combination of leptin and caerulein. We conclude that: 1. Gene expression for HSP60 has been detected in pancreatic AR42J cells under basal conditions. 2. HSP60 gene expression was significantly increased in pancreatic AR42J cells stimulated by leptin whereas caerulein reduced this signal. 3. The strongest gene expression for HSP60 has been detected in the cells incubated with combination of caerulein and leptin.

2

Increase of heat shock protein gene expression by melatonin in AR42J cells

100%

Bonior J., Jaworek J., Konturek S. J., Pawlik W. W.

Journal of Physiology and Pharmacology

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2005

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tom 56

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nr 3

Heat shock proteins (HSPs) have been reported to protect the pancreatic cells from the acute damage produced by caerulein overstimulation. However the effects of caerulein, melatonin or hyperthermia preconditioning on mRNA signal for HSP60 in the pancreatic acinar cells has not been examined yet. The aims of this study were: 1. To investigate the gene expression for HSP60 in the pancreatic AR42J cells stimulated by melatonin, caerulein or combination of both these substances. 2. To compare above changes with mRNA signal for HSP60 in pancreatic AR42J cells subjected to hyperthermia preconditioning. AR42J cells were incubated in standard medium at 37°C for: 0, 1, 3, 5, 12 or 24 h, under basal conditions. Above cells were then subjected to heat shock (42°C) for 0, 1 or 3 h. In the next part of the study AR42J cells were incubated in presence of caerulein (10-11, 10-9 or 10-7M), melatonin (10-8 or 10-6M), or combination of above under basal conditions or following heat shock pretreatment. Gene expression for HSP60 was determined by RT-PCR. The mRNA signal for HSP60 has been observed in AR42J cells under basal conditions, and this signal was markedly and time-dependently increased in these cells subjected to hyperthermia preconditioning. Incubation of AR42J cells in presence of melatonin (10-8 or 10-6M) resulted in the significant and dose-dependent increase of gene expression for HSP60 in both groups of AR42J cells: preconditioned and in those, which were not subjected to hyperthermia. Caerulein stimulation reduced mRNA signal for HSP60. The strongest signal has been observed after the exposition of AR42J cells to hyperthermia preconditioning, combined with melatonin and caerulein. We conclude that: 1. Gene expression for HSP60 has been detected in pancreatic AR42J cells under basal conditions. 2. Hyperthermia preconditioning resulted in a significant and time-dependent increase of HSP60 signal in pancreatic AR42J cells. 3. HSP60 gene expression was significantly increased in pancreatic AR42J cells stimulated by melatonin whereas caerulein reduced this signal. 4. The strongest gene expression for HSP60 has been found in the cells subjected to the combination of hyperthermia preconditioning, caerulein and melatonin.

3

Endotoxemia in the infant rats modulates HSP60 protein level in the pancreatic acinar cells

88%

Bonior J., Jaworek J., Kot M., Konturek S. J., Pawlik W. W.

Journal of Physiology and Pharmacology. Supplement

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2007

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tom 58

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nr 3

189-198

4

Role of leptin in the control of postprandial pancreatic enzyme secretion

76%

Jaworek J., Bonior J., Konturek S. J., Bilski J., Szlachcic A., Pawlik W. W.

Journal of Physiology and Pharmacology

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2003

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tom 54

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nr 4

Leptin released by adipocytes has been implicated in the control of food intake but recent detection of specific leptin receptors in the pancreas suggests that this peptide may also play some role in the modulation of pancreatic function. This study was undertaken to examine the effect of exogenous leptin on pancreatic enzyme secretion in vitro using isolated pancreatic acini, or in vivo in conscious rats with chronic pancreatic fistulae. Leptin plasma level was measured by radioimmunoassay following leptin administration to the animals. Intraperitoneal (i.p.) administration of leptin (0.1, 1, 5, 10, 20 or 50 µg/kg), failed to affect significantly basal secretion of pancreatic protein, but markedly reduced that stimulated by feeding. The strongest inhibition has been observed at dose of 10 µg/kg of leptin. Under basal conditions plasma leptin level averaged about 0.15 ± 0.04 ng/ml and was increased by feeding up to 1.8 ± 0.4 ng/ml. Administration of leptin dose-dependently augmented this plasma leptin level, reaching about 0.65 ± 0.04 ng/ml at dose of 10 µg/kg of leptin. This dose of leptin completely abolished increase of pancreatic protein output produced by ordinary feeding, sham feeding or by diversion of pancreatic juice to the exterior. Leptin (10-10-10-7 M) also dose-dependently attenuated caerulein-induced amylase release from isolated pancreatic acini, whereas basal enzyme secretion was unaffected. We conclude that leptin could take a part in the inhibition of postprandial pancreatic secretion and this effect could be related, at least in part, to the direct action of this peptide on pancreatic acini

5

Melatonin as modulator of pancreatic enzyme secretion and pancreatoprotector

64%

Jaworek J., Nawrot-Porabka K., Leja-Szpak A., Bonior J., Szklarczyk J., Kot M., Konturek S. J., Pawlik W. W.

Journal of Physiology and Pharmacology. Supplement

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2007

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tom 58

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nr 6

6

The dynamics of heat shock system activation in Monomac-6 cells upon Helicobacter pylori infection

64%

Pierzchalski P., Jastrzebska M., Link-Lenczowski P., Leja-Szpak A., Bonior J., Jaworek J., Okon K., Wojcik P.

Journal of Physiology and Pharmacology

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2014

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tom 65

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nr 6

7

Kynuramines induce overexpression of heat shock proteins in pancreatic cancer cells via 5-hydroxytryptamine and melatonin MT1/MT2 receptors

64%

Leja-Szpak A., Pierzchalski P., Goralska M., Nawrot-Porabka K., Bonior J., Link-Lenczowski P., Jastrzebska M., Jaworek J.

Journal of Physiology and Pharmacology

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2015

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tom 66

|

nr 5

8

Melatonin metabolite, N1-acetyl-N1-formyl-5-methoxykynuramine (AFMK), attenuates acute pancreatitis in the rat: in vivo and in vitro studies

64%

Jaworek J., Szklarczyk J., Bonior J., Kot M., Goralska M., Pierzchalski P., Reiter R. J., Czech U., Tomaszewska R.

Journal of Physiology and Pharmacology

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2016

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tom 67

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nr 3

9

Effect of neonatal endotoxemia on the pancreas of adult rats

64%

Jaworek J., Leja-Szpak A., Nawrot-Porabka K., Bonior J., Szklarczyk J., Kot M., Konturek S. J., Tomaszewska R., Pawlik W. W.

Journal of Physiology and Pharmacology. Supplement

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2008

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tom 59

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nr 4

87-102

10

Effect of central administration of L-tryptophan [melatonin precursor] and luzindole [melatonin MT2 receptor antagonist] on the course of caerulein induced acute pancreatitis in the rat

64%

Nawrot K., Jaworek J., Bonior J., Leja-Szpak A., Kot M., Sendur R., Pawlik W. W., Konturek S. J.

Journal of Physiology and Pharmacology. Supplement

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2001

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tom 52

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nr 2

11

Role of endogenous melatonin and its MT2 receptor in the modulation of caerulein-induced pancreatitis in the rat

64%

Jaworek J., Konturek S. J., Leja-Szpak A., Nawrot K., Bonior J., Tomaszewska R., Stachura J., Pawlik W. W.

Journal of Physiology and Pharmacology

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2002

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tom 53

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nr 4,2

The present study investigated the involvement of endogenous melatonin in the prevention of pancreatic damage provoked by caerulein-induced pancreatitis (CIP) by using the luzindole, the antagonist of melatonin MT2 receptors. CIP was produced by subcutaneous infusion of caerulein to conscious rats (25 µg/kg). Luzindole (1, 2 or 4 mg/kg) was given as an intraperitoneal bolus injection 30 min prior to the start of CIP. Lipid peroxidation products, malondialdehyde (MDA) and 4- hydroxynonenal (4-HNE) were measured in the pancreas by LPO-584 commercial kit. CIP was confirmed by histological examination and manifested by significant increases of plasma activities of amylase, lipase and tumor necrosis factor a (TNFalpha) (by 500%, 1000% and 600%, respectively) comparing to the control values. This was accompanied by a 40% limitation in pancreatic blood flow (PBF) and by 200% increase of MDA+4-HNE in the pancreas of CIP rats. Administration of luzindole to the CIP rats reduced PBF, aggravated the histological manifestations of pancreatitis, resulted in the significant augmentation of pancreatic MDA + 4-HNE content, and produced the marked increases of plasma levels of lipase, amylase and TNFalpha, comparing to the values observes in the rats with CIP alone. These results suggest that endogenous melatonin through its receptor MT2 plays an important role in the attenuation of pancreatic damage produced by overstimulation with caerulein.

12

Sensory nerves in central and peripheral control of pancreatic integrity by leptin and malatonin

64%

Jaworek J., Bonior J., Leja-Szpak A., Nawrot K., Kot M., Tomaszewska R., Stachura J., Pawlik W. W., Konturek S. J.

Journal of Physiology and Pharmacology

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2002

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tom 53

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nr 1

Central nervous system affects pancreatic secretion of enzymes however,the neural modulation of acute pancreatitis has not been investigated.Leptin and melatonin have been recently reported to affect the inflammatory response of various tissues.The identification of specific receptors for both peptides in the pancreas suggests that leptin and melatonin could contribute to the pancreatic protection against inflammation.The aim of this study was:1/to compare the effect of intracerebroventricular (i.c.v.)or intraperitoneal (i.p.) administration of leptin or melatonin on the course of caerulein-induced pancreatitis (CIP) in the rat,2/to examine the involvement of sensory nerves (SN)and calcitonin gene-related peptide (CGRP)in pancreatic protection afforded by leptin or melatonin,3/to assess the effect of tested peptides on lipid peroxidation products (MDA +4-HNE)in the pancreas of CIP rats,4/to investigate the influence of leptin or melatonin on nitric oxide (NO)release from isolated pancreatic acini and 5/to determine the effects of caerulein and leptin on leptin receptor gene expression in these acini by RT-PCR.CIP was induced by subcutaneous (s.c.)infusion of caerulein (25 µg/kg)to the conscious rats,confirmed by the significant increases of pancreatic weight and plasma amylase and by histological examination.This was accompanied in marked reduction of pancreatic blood flow and significant rise of MDA +4-HNE in the pancreas.Leptin or melatonin were administered i.p.or i.c.v.30 min prior to the start of CIP.Deactivation of SN was produced by s.c.capsaicin (100 mg/kg).An antagonist of CGRP,CGRP8-37 (100 µg/kg i.p.),was given together with leptin or melatonin to the CIP rats.MDA +4-HNE was measured using LPO commercial kit.NO was determined using the Griess reaction.Pretreatment of CIP rats with i.p.leptin (2 or 10 µg/kg)or melatonin (10 or 50 mg/kg)significantly attenuated the severity of CIP.Similar protective effects were observed following i.c.v.application of leptin (0.4 or 2 µg/rat)but not melatonin (10 or 40 µg/rat)to the CIP rats.Capsaicin deactivation of SN or administration of CGRP8-37 abolished above beneficial effects of leptin on CIP,whereas melatonin-induced protection of pancreas was unaffected.Pretreatment with i.p.melatonin (10 or 50 mg/kg),but not leptin,significantly reduced MDA +4-HNE in the pancreas of CIP rats.Leptin (10–9 -10–6 M)but not melatonin (10–8 -10–5 M)significantly stimulated NO release from isolated pancreatic acini.Leptin receptor gene expression in these acini was significantly increased by caerulein and leptin. We conclude that 1/central or peripheral pretreatment with leptin protects the pancreas against its damage induced by CIP,whereas melatonin exerts its protective effect only when given i.p.,but not following its i.c.v.adminstration,2/activation of leptin receptor in the.pancreatic acini appears to be involved in the beneficial effects of leptin on acute pancreatitis, 3/the protective effects of leptin involve sensory nerves,CGRP and increased generation of NO whereas melatonin-induced protection of the pancreas depends mainly on the antioxidant local effect of this indole,and scavenging of the radical oxygen species in the pancreatic tissue.

13

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Protective role of endogenous nitric oxide (NO) in lipopolysaccharide - induced pancreatic damage. (A new experimental model of acute pancreatitis)

64%

Jaworek J., Jachimczak B., Bonior J., Kot M., Tomaszewska R., Karczewska E., Stachura J., Pawlik W., Konturek S. J.

Journal of Physiology and Pharmacology

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2000

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tom 51

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nr 1

14

Exposition of newborn rats to bacterial endotoxin impairs pancreatic enzyme secretion at adult age

64%

Jaworek J., Nawrot-Porabka K., Leja-Szpak A., Szklarczyk J., Macko M., Bonior J., Stachura J., Konturek S. J., Pawlik W. W.

Journal of Physiology and Pharmacology

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2007

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tom 58

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nr 2

Lipopolysaccharide (LPS, endotoxin) is the component of the cellular wall of Gram negative bacteria. Endotoxemia (sepsis) could produce multiorgan failure and in the early period of life LPS are responsible for the changes of metabolism and for the reduction of protein synthesis. The influence of neonatal endotoxemia on the pancreas at adults has not been investigated yet. The aim of this study was to assess the pancreatic exocrine function in the adult rats which have been subjected, in the neonatal period of life, to chronic LPS pretreatment. LPS from E. coli or S. typhi at doses of 5, 10 or 15 mg/kg-day was administered intraperitoneally (i.p.) to the suckling rats (30 g) during 5 consecutive days. Three months later these animals (300 g) were equipped with pancreato-biliary fistulae for the in vivo secretory study. Amylase release from isolated pancreatic acini obtained from these rats was also assessed. Pancreatic tissue samples were taken for histological assessment and for the determination of gene expression for CCK1 receptor by RT-PCR. Pancreatic amylase secretions stimulated by caerulein or by diversion of pancreatic-biliary juice to the exterior (DBPJ) was significantly, and dose-dependently reduced in the adult rats which have been subjected in infancy to chronic pretreatment with LPS from E. coli or S. typhi, as compared to the untreated control. In these animals basal secretion was unaffected. In the rats pretreated with LPS in the suckling period of life caerulein-induced amylase release from isolated pancreatic acini was significantly decreased, as compared to the untreated with LPS control. This was accompanied by dose-dependent reduction of mRNA signal for CCK1 receptor on pancreatic acini. Neonatal endotoxemia failed to affect significantly pancreatic morphology as well as plasma amylase level in the adult rats. We conclude that neonatal endotoxemia reduces gene expression for CCK1 receptor and could produce impairment of the exocrine pancreatic function at adult age.

15

Leptin is involved in the protective effect of lipopolysaccharide [LPS] in the caerulein-induced pancreatitis

64%

Bonior J., Jaworek J., Leja-Szpak A., Nawrot K., Kot M., Bielanski W., Sendur R., Pawlik W. W., Konturek S. J.

Journal of Physiology and Pharmacology. Supplement

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2001

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tom 52

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nr 2

16

Involvement of cyclooxygenase-derived prostaglandin E2 and nitric oxide in the protection of rat pancreas afforded by low dose of lipopolysaccharide

52%

Jaworek J., Bonior J., Tomaszewska R., Jachimczak B., Kot M., Bielanski W., Pawlik W. W., Sendur R., Stachura J., Konturek P. C., Konturek S. J.

Journal of Physiology and Pharmacology

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2001

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tom 52

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nr 1

17

Melatonin precursor, L-tryptophan protects the pancreas from development of acute pancreatitis through the central site of action

52%

Leja-Szpak A., Jaworek J., Tomaszewska R., Nawrot K., Bonior J., Kot M., Palonek M., Stachura J., Czupryna A., Konturek S. J., Pawlik W. W.

Journal of Physiology and Pharmacology

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2004

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tom 55

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nr 1,2

Melatonin, produced from L-tryptophan, protects the pancreas against acute damage by improving the antioxidative status of tissue. Melatonin receptors have been detected in the brain, but the contribution of these receptors to the pancreatic protection is unknown. The aim of our study was to compare the effects of melatonin precursor; L-tryptophan given intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) on the course of acute pancreatitis. Acute pancreatitis was induced by subcutaneous infusion of caerulein (5µg/kg-h x 5h). L-tryptophan was given i.p. (2.5, 25 or 250 mg/kg) or administered into right cerebral ventricle (0.02, 0.2 or 2.0 mg/rat) 30 min prior to the start of caerulein infusion. Plasma amylase, lipase and TNF alpha activities were measured to determine the severity of caerulein-induced pancreatitis (CIP). The lipid peroxidation products: malonylodialdehyde and 4-hydroksynonenal (MDA + 4-HNE) and activity of superoxide dismutase (SOD) were measured in the pancreas of intact or CIP rats with or without L-tryptophan pretreatment. Melatonin blood level was measured by RIA. CIP was confirmed by histological examination and manifested as an edema and rises of plasma levels of amylase, lipase and TNF alpha (by 550%, 1000% and 600%). MDA + 4-HNE was increased by 600%, whereas SOD activity was reduced by 75% in the pancreas of CIP rats. All manifestations of CIP were significantly reduced by pretreatment of the rats with L-tryptophan given i.c.v. at doses of 0.2 or 2.0 mg/rat, or by peripheral administration of this amino acid used at dose of 250 mg/kg i.p. In control rats plasma level of melatonin averaged about 40 ± 2 pg/ml and was not significantly affected by CIP, by central application of L-tryptophan (0.02, 0.2 or 2.0 mg/rat) or by peripheral administration of this melatonin precursor used at doses of 2.5 or 25 mg/kg i.p. Plasma melatonin level was markedly increased by pretreatment of the rats with L-tryptophan given i.p. at dose of 250 mg/kg. We conclude that central administration of melatonin precursor; L-tryptophan, as well as peripheral application of high dose of this melatonin precursor prevented the pancreatic damage produced by CIP. The favorable effect of peripherally administered L-tryptophan could be related to the rise of melatonin plasma level and to pancreatoprotective action of this indoleamine. The beneficial effect of centrally administered L-tryptophan could be mediated through activation of central receptors for locally produced melatonin.

Ograniczanie wyników

Leptin is the modulator of HSP60 gene expression in AR42J cells

Increase of heat shock protein gene expression by melatonin in AR42J cells

Endotoxemia in the infant rats modulates HSP60 protein level in the pancreatic acinar cells

Role of leptin in the control of postprandial pancreatic enzyme secretion

Melatonin as modulator of pancreatic enzyme secretion and pancreatoprotector

The dynamics of heat shock system activation in Monomac-6 cells upon Helicobacter pylori infection

Kynuramines induce overexpression of heat shock proteins in pancreatic cancer cells via 5-hydroxytryptamine and melatonin MT1/MT2 receptors

Melatonin metabolite, N1-acetyl-N1-formyl-5-methoxykynuramine (AFMK), attenuates acute pancreatitis in the rat: in vivo and in vitro studies

Effect of neonatal endotoxemia on the pancreas of adult rats

Effect of central administration of L-tryptophan [melatonin precursor] and luzindole [melatonin MT2 receptor antagonist] on the course of caerulein induced acute pancreatitis in the rat

Role of endogenous melatonin and its MT2 receptor in the modulation of caerulein-induced pancreatitis in the rat

Sensory nerves in central and peripheral control of pancreatic integrity by leptin and malatonin

Protective role of endogenous nitric oxide (NO) in lipopolysaccharide - induced pancreatic damage. (A new experimental model of acute pancreatitis)

Exposition of newborn rats to bacterial endotoxin impairs pancreatic enzyme secretion at adult age

Leptin is involved in the protective effect of lipopolysaccharide [LPS] in the caerulein-induced pancreatitis

Involvement of cyclooxygenase-derived prostaglandin E2 and nitric oxide in the protection of rat pancreas afforded by low dose of lipopolysaccharide

Melatonin precursor, L-tryptophan protects the pancreas from development of acute pancreatitis through the central site of action