Wyniki wyszukiwania - Biblioteka Nauki

1

Inhibition of Barrett's adenocarcinoma cell growth by simvastatin: involvement of COX-2 and apoptosis-related proteins

100%

Konturek P. C. , Burnat G. , Hahn E. G.

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2007

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tom 58

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nr 3

141-148

2

NO-releasing aspirin exerts stronger growth inhibitory effect on Barrett's adenocarcinoma cells than traditional aspirin

100%

Konturek P. C. , Kania J. , Burnat G. , Hahn E. G.

Journal of Physiology and Pharmacology. Supplement

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2006

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tom 57

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nr 12

15-24

EN

Expression of cyclooxygenase-2 (COX-2) is involved in the chronic inflammation-related development of Barrett’s adenocarcinoma and the use of selective COX-2 inhibitors (coxibs) might provide new chemoprevention strategy for Barrett’s adenocarcinoma (BA). Despite an excellent gastrointestinal (GI) safety profile of coxibs, their use is limited because of the possible cardiovascular complications. The coupling of NSAIDs with a NO-donating moiety has led to the birth of a new class of anti-inflammatory drugs, called the COX-inhibiting nitric oxide donators (CINODs). The member of this group, NO-aspirin (NO-ASA) retains the anti-inflammatory properties of traditional aspirin (ASA), but the release of NO accounts for anti-thromboembolic effect and better GI safety profile. The role of NO-ASA in the prevention of Barrett’s adenocarcinoma (BA) has not been studied so far. Therefore, the aim of the present study was: 1) to analyse the expression of COX-2 in the biopsies obtained from BE; 2) to compare the effect of NO-ASA with that of ASA on proliferation rate in Barrett’s adenocarcinoma cell line (OE-33 cells); 3) to determine the effect of both compounds on the apoptosis rate using FACS analysis and expression of 32-kDa procaspase-3 and active proapoptotic 20-kDa caspase-3 in OE-33 cell line. The expression of COX-2 was assessed in biopsies obtained from the Barrett’s mucosa and normal squamous epithelial esophageal mucosa from 20 BE patients by RT-PCR and Western blot analysis, respectively. The BA cell line (OE-33) was incubated with NO-ASA or ASA (10-1000µM). The cell proliferation and apoptosis rate was measured by BrdU and FACS-analysis, respectively. The expression of caspase-3 (active and inactive form) was analyzed by Western blot. In Barrett’s mucosa a significant up-regulation of COX-2 was observed. Compared with traditional ASA, NO-ASA caused a significantly stronger induction of apoptosis (dose-dependently). Inhibition of cell proliferation in OE-33 cells observed under NO-ASA treatment was due to the apoptosis induction. The increase in apoptotic rate was accompanied by the upregulation of active 20-kDa caspase-3. At the highest concentration (1000µM), a necrotic death of OE-33 cells was observed under NO-ASA treatment. We conclude that: NO-ASA caused induction of apoptosis in BA cell line and slight growth inhibition. These results indicate that this compound may represent a promising chemopreventive agent for Barrett’s adenocarcinoma.

3

Bile acids are multifunctional modulators of the Barrett’s carcinogenesis

100%

Burnat G. , Majka J. , Konturek P. C.

Journal of Physiology and Pharmacology

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2010

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tom 61

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nr 2

EN

Bile salts play an important pathogenic role in the development of Barrett adenocarcinoma (BA). However, the precise role of different bile salts in this process is still unknown. The aim of the present study was to compare the effects of two different bile salts, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) on the expression of COX-2, CDX-2 and DNA repair enzymes (MUTYH, OGG-1) in the Barrett epithelial cancer cells (OE-19). OE-19 cells were incubated with DCA or UDCA (100 µM or 300 µM at pH=7.0) over 24 h. To investigate the involvement of NFB, in separate experiments the cells were incubated with DCA in the presence of proteosome inhibitor (MG-132). Cells cycle and apoptosis were analyzed by FACS analysis. After incubation of OE-19 cells with bile salts, the expression of mRNA of COX-2, DNA repair enzymes (MUTYH, OGG-1) and caudal-related homebox transcription factor CDX-2 were measured by quantitative RT-PCR. OE-19 cell were also transfected with siRNA-RelA (p65) to asses effect of NFB inactivation on COX-2 and CDX2 expression. DCA caused a stronger reduction in cell survival of OE-19 cells than UDCA. In addition, DCA stimulated directly the translocation of NFB p65 (active form) in the nuclei of OE-19 cells. DCA caused stronger than UDCA stimulation of the COX-2 mRNA expression in these cells and this effect was significantly attenuated by the addition of inhibitor of NFB activity (proteosome inhibitor MG-132). siRNA-RelA reduced expression not only of NFB but also expression of COX-2 as well as CDX-2 mRNA. DCA caused stronger downregulation of mRNA for DNA repair enzymes MUTYH and OGG-1 than UDCA. In contrast, UDCA induced stronger CDX-2 mRNA expression than DCA in OE-19 cells. We conclude that bile salts are involved in the carcinogenesis of Barrett adenocarcinoma via inhibition of DNA repair enzymes and induction of COX-2 and this last effect is, at least partly, mediated by NFB. DCA shows carcinogenic potential due to high upregulation of COX-2, CDX-2 and downregulation of DNA repair enzymes.

4

Prostaglandins as mediators of COX-2 derived carcinogenesis in gastrointestinal tract

88%

Konturek P. C. , Kania J. , Burnat G. , Hahn E. G. , Konturek S. J.

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nr 5

57-73

EN

This review was designed to show the role of expression of cyclooxygenase (COX)-1 and COX-2 in the cancerogenesis of esophagus, stomach and colon. Unlike COX-1, which is expressed in the normal esophageo-gastro-colonic mucosa, COX-2 was found to be expressed mainly in the pre-cancer changes in the mucosa including Barrett's esophagus, Helicobacter pylori (H. pylori)-induced gastritis and inflammatory changes in colonic mucosa. In Barrett's esophagus, prostaglandins (PGs) derived from upregulated COX-2 contribute to the progression of low-grade to high-grade dysplasia and finally to cancer. In chronic gastritis induced by chronic H. pylori infection, overexpression of COX-2 is probably induced by inflammatory cytokines, growth factors, especially gastrin and reactive oxygen species leading to mutagenesis and subsequent metaplasia, dysplasia and cancer formation. The imbalance between cell proliferation and apoptosis caused mainly by products of COX-2 leads to cancerogenesis. Similarly, in colorectal cancer the overexpression of COX-2, possibly induced by the action of growth promoting factors including progastrin and gastrin and overexpression of survivin contribute to the colorectal cancerogenesis that could be, at least in part, amended by the treatment with specific COX-2 inhibitors. We conclude that: 1) COX-2-derived PGs play a key role in the tumorogenesis in the gastrointestinal tract; 2) The tumor-promoting effect of PGs may be attributed to their ability to stimulate cell proliferation and migration, to inhibit the apoptosis and to increase angiogenesis and invasiveness; 3) In accordance to the proposed major role of COX-2 in cancerogenesis, selective COX-2 inhibitors have been shown in numerous studies to exhibit strong chemopreventive effect on the development of gastrointestinal cancers.

5

Tryptophan free diet delays healing of chronic gastric ulcers in rat

88%

Konturek P. C. , Burnat G. , Brzozowski T. , Zopf Y. , Konturek S. J.

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nr 2

EN

Melatonin (MT) is an ubiquitous molecule, representing one of the phylogenetically oldest signaling mechanisms. Our previous studies demonstrated that MT and its precursor L-tryptophan (L-Trp) show strong protective effect on gastric mucosa. The aim of the present study was: 1) to assess the effect of MT and L-Trp on healing of chronic gastric ulcer and accompanying changes in gastric mucosal blood flow (GBF); 2) to study the effect of MT and L-Trp on expression of iNOS. cNOS and HSP70 in ulcerated mucosa; 3) to compare the effect of L-Trp free and L-Trp rich diet on ulcer healing and gene expression of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-), superoxide dismutase (SOD), cyclooxygenase-2 (COX-2) and NFkappaB-p65 protein expression in ulcer area and intact non-ulcerated. Chronic ulcers were induced in Wistar rats by Okabe’s modification of acetic acid method. Rats with chronic gastric ulcers were divided in following treatment groups: 1) vehicle (saline); 2) MT (20mg/kg-d i.p.) and 3) L-Trp (100 mg/kg i.p.). The expression of iNOS, cNOS and HSP70 protein was measured by Western blot. In separate experiments, the influence of commercially available (Bio-Serv, USA) L-Trp free diet (TFD) was compared to the L-Trp rich diet (TRD) on the course of ulcer healing was assessed. The ulcer area was measured by planimetry. The expression of TNF, COX-2 and SOD mRNA in ulcerated mucosa was analyzed by RT-PCR method. MT and its precursor L-Trp significantly accelerated ulcer healing. Healing ulcerated mucosa showed increased protein expression of iNOS and HSP70 as compared to intact gastric mucosa. TFD in contrast to normal diet significantly attenuated the ulcer healing, whereas the TRD exerted opposite effects and significantly accelerated ulcer healing. This last effect was accompanied by significant decrease of TNF- mRNA expression and expression of NFkB-p65 in gastric mucosa. We conclude that: 1) MT and its precursor L-Trp significantly accelerate healing of gastric ulcer; 2) L-Trp free diet significantly attenuates experimental ulcer healing and this is due to decreased synthesis of MT from L-Trp by EE cells in gastric mucosa and 3) MT shows strong anti-inflammatory effects due to inhibition of NFkappaB and TNF- expression.

6

Probiotic bacteria Escherichia coli strain Nissle 1917 attenuates acute gastric lesions induced by stress

75%

Konturek P. C. , Sliwowski Z. , Koziel J. , Ptak-Belowska A. , Burnat G. , Brzozowski T. , Konturek S. J.

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2009

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tom 60

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nr 6

7

Ulcerative colitis in AKR mice is attenuated by intraperitoneally administered anandamide

75%

Engel M. A. , Kellermann C. A. , Rau T. , Burnat G. , Hahn E. G. , Konturek P. C.

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nr 4

673-689

EN

Anti-inflammatory and anti-nociceptive properties of endocannabinoids and synthetic cannabinoid compounds were described previously. We studied effects of the endogenous cannabinoid anandamide (N-arachidonylethanolamine) in experimental colitis induced by TNBS (2,4,6-trinitrobenzene sulfonic acid) in AKR mice. A scoring system was used to describe clinical and macroscopic changes. Intraperitoneally administered anandamide significantly reduced experimental colitis, quantified by macroscopical and histological scoring systems as well as pro-inflammatory cytokine mRNA expression. We conclude that systemically administered anandamide attenuates TNBS colitis in mice, and that systemically active cannabinoid compounds might have therapeutic potential for the treatment of IBD.

8

Role of brain-gut axis in healing of gastric ulcers

75%

Konturek P. C. , Brzozowski T. , Burnat G. , Kwiecien S. , Pawlik T. , Hahn E. G. , Konturek S. J.

Journal of Physiology and Pharmacology

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2004

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tom 55

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nr 1,2

EN

The previous studies demonstrated the pivotal role of capsaicin-sensitive peptidergic sensory neurons and vagal nerves in the maintenance of gastric mucosal integrity. The aim of the present study was: 1) to examine the effect of the functional ablation of sensory neurons with neurotoxic dose of capsaicin and surgical vagotomy on the course of healing of gastric ulcer in rat, and 2) to compare the ulcer healing action of leptin in rats with or without capsaicin-induced inactivation of sensory neurons. Three series of experiments (A, B and C) were performed in Wistar rats with gastric ulcers induced by acetic acid method. In series A, the course of ulcer healing was compared in rats with intact and capsaicin-inactivated sensory neurons. In the series B, the effect of vagotomy on the ulcer healing and accompanying changes in GBF were determined at day 8 and 16 after ulcer induction. The rats of series C, consisting of animals with intact nerves or those with capsaicin-denervation, received the 7-day treatment with exogenous leptin (10 µg/kg i.p. twice daily) to check whether blockade of sensory nerves could influence the acceleration of ulcer healing by this peptide. Capsaicin-induced ablation of sensory neurons significantly delayed ulcer healing and this was accompanied by the significant fall in the GBF and the significant rise in the gastric mucosal gene expression of IL-1ß and TNF-alpha. Vagotomy significantly delayed ulcer healing and led to decrease in GBF at ulcer margin. Treatment with exogenous leptin significantly accelerated ulcer healing, increased the GBF at ulcer margin and upregulated mRNA for iNOS and these effects were attenuated in rats with capsaicin-deactivation of sensory neurons. We conclude that: 1) vagal and sensory neurons contribute to the gastric ulcer healing process possibly due to the increase of GBF, the limitation of inflammatory response, and overexpression of TGFalpha and iNOS resulting in NO release, and 2) the acceleration of ulcer healing by leptin was attenuated in animals with capsaicin-denervation suggesting an involvement of neuropeptides released from sensory afferent nerves in the ulcer healing effect of this hormone.

9

Ghrelin ameliorates colonic inflammation. Role of nitric oxide and sensory nerves.

63%

Konturek P. C. , Brzozowski T. , Engel M. , Burnat G. , Gaca P. , Kwiecien S. , Pajdo R. , Konturek S. J.

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nr 2

41-47

EN

Ghrelin is a novel growth hormone (GH)-releasing and orexigenic peptide with anti-inflammatory activities. However, the role of ghrelin in the colonic inflammation is still controversial. The aim of the present study was: 1) to examine the expression of ghrelin and TNF- mRNA in the inflamed colonic mucosa of patients with ulcerative colitis (UC), 2) to analyze the effect of treatment with exogenous ghrelin on the healing of trinitrobenze sulphonic acid (TNBS)-induced colitis in rats, and 3) to assess the effects of ghrelin treatment on mRNA expression for iNOS and protein expression for COX-2 and PPAR in intact colonic mucosa and in that with TNBS-induced colitis. Fifteen patients with UC and fifteen healthy controls were enrolled in this study. Expression of ghrelin and TNF- was assessed by semi-quantitative RT-PCR in the colonic mucosal biopsies from UC patients and healthy controls. In addition, the effect of exogenous ghrelin on healing of TNBS colitis was tested in rats without or with capsaicin-induced functional ablation of sensory nerves. Patients with UC showed a significant upregulation of mRNA for ghrelin and TNF- in colonic mucosa as compared to that observed in healthy controls. The expression of ghrelin correlated with the grade of inflammation and expression of TNF-. In rats the exogenous ghrelin administered daily at a dose of 20 µg/kg i.p. significantly accelerated the healing of TNBS colitis and this effect was accompanied by an increase in mRNA expression for iNOS and protein expression for COX-2 in the colonic mucosa. The protein expression for PPAR, which was down-regulated in rat colonic mucosa after exposure to TNBS as compared to that in intact colonic mucosa, was not significantly influenced by ghrelin treatment. We conclude that 1) patients with UC show an increased mucosal expression of mRNA for ghrelin in the colonic mucosa which could trigger protective response in inflamed colon; and 2) exogenous ghrelin accelerates healing of colonic lesions in animal model of ulcerative colitis via increased release of NO and PGE2 due to an increase in iNOS and COX-2 expression and stimulation of sensory neuropeptides such as CGRP released from sensory afferent endings.

10

Gastric ulcer healing and stress-lesion preventive properties of pioglitazone are attenuated in diabetic rats

63%

Konturek P. C. , Brzozowski T. , Burnat G. , Szlachcic A. , Koziel J. , Kwiecien S. , Konturek S. J. , Harsch I. A.

Journal of Physiology and Pharmacology

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2010

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tom 61

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nr 4

429-436

EN

Diabetes mellitus increases susceptibility to acute gastric injury and impairs ulcer healing. Pioglitazone as an agonist of peroxisome proliferator-activated receptor gamma (PPAR) is used as anti-diabetic drug and has additionally gastroprotective activities. However, the effect of pioglitazone on the protection and healing of gastric mucosa under diabetic conditions is poorly understood. The aim of the present study was: 1) to compare the effects of treatment with PPAR ligand (pioglitazone) on healing of acetic acid-induced gastric ulcers and prevention of acute water immersion and restraint stress (WRS)-induced gastric lesions in normal rats and those with streptozotocin (STZ)-induced diabetes mellitus; 2) to assess the effects of pioglitazone on the mRNA expression of cyclooxygenase-2 (COX-2), c-NOS, interleukin-1ß and hypoxia inducible factor-1 alpha (HIF-1) in the gastric mucosa of rats with or without STZ-induced diabetes mellitus; 3) to investigate the involvement of endogenous NO and proinflammatory cytokines (IL-1ß, TNF-) in healing of chronic gastric ulcers and in prevention of acute stress lesions by pioglitazone in rats with or without STZ-induced diabetes mellitus. Diabetes was induced in rats by single injection of STZ (70 mg/kg i.p.) four weeks prior to production of gastric ulcers by acetic acid method or induction of stress lesions by 3.5 hours of WRS. Non-diabetic rats were used as controls. Two major animal groups (A and B) were tested; A) diabetic and non-diabetic rats with chronic gastric ulcers treated with 1) pioglitazone (40 mg/kg-d i.g.), 2) pioglitazone in combination of blocker of NO synthase (L-NNA 20 mg/kg-d i.p.), and 3) saline (vehicle-control); and B) diabetic and non-diabetic rats exposed to 3.5 hours of WRS and pretreated with 1) pioglitazone (40 mg/kg i.g.), 2) pioglitazone in combination of blocker of NO synthase (L-NNA 20 mg/kg i.p.), and 3) saline (vehicle-control). The gastric mucosal blood flow was assessed by H2-gas clearance method. The area of chronic acetic acid ulcers and number of acute WRS-induced gastric lesions were assessed by planimetry or by counting of number of lesions, respectively. In rats with chronic ulcers, the mRNA expression of HIF-1, IL-1ß and COX-2 was assessed by RT-PCR and protein expression of platelet endothelial cell adhesion molecule-1 (PECAM-1), COX-2 and cNOS was examined by Western blot. In rats with stress lesions, the protein expression of COX-2, cNOS, catalase, PPAR and heat shock protein 70 (HSP70) was examined by Western blot. In diabetic rats, a marked delay in ulcer healing and increased susceptibility to WRS lesions were observed and these effects were accompanied by a significant decrease in GBF. Pioglitazone significantly increased healing of chronic gastric ulcers and exerted a strong protective effect against WRS-induced lesions, but these effects were attenuated by NO-inhibition with L-NNA. Interestingly, the ulcer healing and gastroprotective effects of pioglitazone were weak under diabetic conditions, and this effect on ulcer healing was accompanied by impaired angiogenesis due to decreased PECAM-1 expression, attenuated expression of COX-2 and the increased expression of proinflammatory cytokines compared to those in diabetic rats treated with vehicle. We conclude that: 1) experimental diabetes in rats impairs healing of chronic ulcers and enhances acute stress lesions due to an increase in the expression and release of proinflammatory cytokines such as TNF- and IL-1ß; 2) the ulcer healing effect of pioglitazone, which is, at least in part, mediated by endogenous NO, is significantly attenuated by L-NNA in diabetic rats despite increased COX-2 expression at the ulcer edge; 3) the formation of acute gastric lesions induced by WRS is also attenuated by pretreatment with pioglitazone due to increased GBF probably mediated by NO, as the administration of L-NNA reversed, in part, the preventive action induced by this PPAR ligand, and 4) pioglitazone is effective both in healing of chronic ulcers and protection against WRS lesions though its action under diabetic conditions seems to be attenuated, possibly due to reduction in NOS-NO system, angiogenesis and increased expression and release of proinflammatory cytokines.

11

Melatonin and its precursors L-tryptophan prevent acute gastric mucosal damage induced by aspirin in humans

63%

Konturek P. C. , Celinski K. , Slomka M. , Cichoz-Lach H. , Burnat G. , Naegel A. , Bielanski W. , Konturek J. W. , Konturek S. J.

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nr 2

EN

Melatonin (MT) and its precursor L-tryptophan (Trp) are implicated in the protection of gastric mucosa against noxious agents. However, the role of MT and Trp on the gastric mucosal injury induced by aspirin (ASA) in human has not been investigated. Studies in animals showed that both MT and Trp given intragastrically prevents the formation of gastric mucosal lesions induced by ASA. The aim of the present study was to determine the influence of MT and Trp given orally to healthy humans on gastric mucosal lesions induced by ASA. The present study included 21 healthy, Hp-negative male volunteers with intact gastro-duodenal mucosa aging 20-50 yr. They were divided in 3 groups; group1: 7 volunteers receiving daily 2 x 1g ASA (Polfa, Rzeszow) during 11 days; group 2: 7 healthy volunteers receiving 2x1g ASA and MT (Lekam, Zakroczyn) (5 mg 30 min prior to ASA) during 11 days and group 3: 7 healthy volunteers receiving 2x1g ASA and Trp (Ardeytropin, Germany) (0.5 g 30 min prior to ASA) during 11 days. Mucosal damage was evaluated at 3rd, 7th and 11th days of ASA administration by endoscopy using Lanza score. Plasma melatonin was measured using RIA and gastric mucosal generation of PGE2 was assessed also by RIA. ASA caused marked mucosal injury at all days of its administration except day 11th when only moderate lesions were evident. Pre-treatment with MT or Trp alone was accompanied by a significant decrease in gastric mucosal lesion score. Gastric mucosal generation of PGE2 was suppressed by about 90% in subjects treated with ASA without or with MT or Trp. We concluded that: MT and its precursor Trp significantly attenuate gastric mucosal lesions induced by aspirin. The action of Trp may be be mediated by MT produced in gastrointestinal tract from Trp. The gastroprotective action of MT and Trp is independent on gastric mucosal PGE2 generation.

12

Gastrin mediated down regulation of ghrelin and its pathophysiological role in atrophic gastritis

51%

Rau T. T. , Sonst A. , Rogler A. , Burnat G. , Neumann H. , Oeckl K. , Neuhuber W. , Dimmler A. , Faller G. , Brzozowski T. , Hartmann A. , Konturek P. C.

Journal of Physiology and Pharmacology

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2013

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tom 64

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nr 6