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1

Helicobacter pylori infection in gastric cancerogenesis

100%

Konturek P. C. , Konturek S. J. , Brzozowski T.

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nr 3

3-21

EN

Gastric cancer (GS) remains one of the most common cancers worldwide. It is considered as the second most frequent cause of cancer death worldwide, although much geographical variation in incidence exists. Many studies before linked Helicobacter pylori (Hp) which is now considered as an important pathogen, to the risk of developing noncardia GS. This overview attempts to summarize the recent basic and clinical evidence on the link between H. pylori and gastric cancer, after the award of the Nobel Prize for Physiology or Medicine to Drs. J.R. Warren and B.J. Marshall for the first culture and isolation of Hp and the investigation of their relevance to peptic ulcer disease. It become evident that Hp eradication by antibiotic treatment combined with proton pump inhibitor (PPI) serves as the primary chemoprevention strategy to reduce gastric cancer incidence. Moreover, the eradication therapy reduces gastric cancer incidence in patients without any precancerous lesions at the baseline and is most effective before the development of atrophic gastritis. Due to understanding the molecular nature of GC which has been nowadays under intense investigation, our review attempts to highlight recent progress in the field of research on Hp-induced GS. We discuss the geographical diversity in Hp infection and cancer incidence and the mechanistic role of gastrin, cyclooxygenase-2 (COX-2), growth factor, nitric oxide (NO)/NO synthase and E-cadherin/beta-cathenin systems, apoptosis and angiogenesis in Hp-induced gastric carcinogenesis. In addition host-related genetic susceptibility and the role of overexpression of a proinflammatory cytokines and their polymorphism is discussed in the relation to the cascade of events such as gastric atrophy, intestinal metaplasia and dysplasia that finally lead to adenocarcinoma.

2

Role of prostaglandins in gastroprotection and gastric adaptation

88%

Brzozowski T. , Konturek P. C. , Konturek S. J. , Brzozowska I. , Pawlik T.

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nr 5

33-55

EN

Since Robert discovery that pretreatment with prostaglandin (PG) applied in non-antisecretory dose can prevent the injury of gastric mucosa induced by necrotizing agents, much attention was paid to the role of these cyclooxygenaxe (COX) products in the mechanism of gastric mucosal integrity and ulcer healing. The ability of exogenous PG to attenuate or even completely prevent mucosal damage caused by corrosive substances such as absolute ethanol, hiperosmolar solutions or concentrated bile has been termed "cytoprotection". Increased generation of endogenous PG in the gastric mucosa exposed to the topical contact with "mild irritant" such as 20% ethanol, 1 mM NaCl or 5 mM taurocholate also prevented gastric injury caused by strong irritants via phenomenon of adaptive cytoprotection. Other mediators such as growth factors, nitric oxide (NO) or calcitonin gene related peptide (CGRP) as well as some gut hormones including gastrin and cholecystokinin (CCK), leptin, ghrelin and gastrin-releasing peptide (GRP) have been also found to protect gastric mucosa against the damage induced by corrosive substances. This protective action of gut hormones has been attributed to the release of PG or activation of sensory nerves because it could be abolished by the pretreatment with indomethacin or large neurotoxic dose of capsaicin and restored by the addition of exogenous PGE2 or CGRP, respectively. Short (5 min) ischemia of the stomach applied before prolonged ischemia-reperfusion (I/R) attenuated markedly the gastric lesions produced by this I/R and also prevented the mucosal damage provoked by necrotizing substances. This protection could be abolished by the pretreatment with non-steroidal anti-inflammatory drugs (NSAID) and was accompanied by an enhamcement of gastric mucosal COX-2 expression and activity. Exposure of gastric mucosa to single insult of acidified aspirin (ASA) causes severe mucosal damage with occurence of multiple haemorrhagic lesions but with repeated application of ASA, the attenuation of mucosal lesions is observed, despite the profound inhibition of PGE2 generation. This phenomenon called "gastric adaptation" does not appear to depend upon endogenous biosynthesis of PG but possibly involves enhanced production of growth factors increasing cell proliferation and mucosal regeneration. Unlike short lived gastroprotection by PG, NO, CGRP, mild irritants or short ischemia, gastric adaptation appears to be long-lasting phenomenon accompanied by increased resistance of the adapted mucosa to subsequent damage induced by corrosive agents.

3

From nerves and hormones to bacteria in the stomach; Nobel prize for achievements in gastrology during last century

88%

Konturek S. J. , Konturek P. C. , Brzozowski T. , Konturek J. W. , Pawlik W. W.

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nr 4

EN

Rapid progress in gastroenterological research, during past century, was initiated by the discovery by W. Prout in early 18th century of the presence of inorganic, hydrochloric acid in the stomach and by I.P. Pavlov at the end of 19th century of neuro-reflex stimulation of secretion of this acid that was awarded by Nobel prize in 1904. Then, J. W. Black, who followed L. Popielski's concept of histamine involvement in the stimulation of this secretion, was awarded second Nobel prize in gastrology within the same century for the identification of histamine H2-receptor (H2-R) antagonists, potent gastric acid inhibitors, accelerating ulcer healing. The concept of H2-R interaction with other receptors such as muscarinic receptors (M3-R), mediating the action of acetylocholine released from local cholinergic nerves, and those mediating the action of gastrin (CCK2-R) on parietal cells, has been confirmed both in vivo studies and in vitro isolated parietal cells. The discovery of H2-R antagonists by Black and their usefulness in control of gastric secretion and ulcer healing, were considered as real breakthrough both in elucidation of gastric secretory mechanisms and in ulcer therapy. Discovery of even more powerful gastric acid inhibitors, proton pump inhibitors (PPI), also highly effective in acceleration of ulcer healing was, however, not awarded Nobel prize. Unexpectedly, two Australian clinical researchers, R.J. Warren and B.J. Marshall, who discovered in the stomach spiral bacteria, named Helicobacter pylori, received the third in past century Nobel prize in gastrology for the finding that this bacterium, is related to the pathogenesis of gastritis and peptic ulcer. They documented that eradication of H. pylori from the stomach, using antibiotics and potent gastric inhibitors, not only accelerates healing of ulcer but also prevents its recurrence, the finding considered as greatest discovery in practical gastrology during last century. Thus, the outstanding achievements in gastroenterology during last century have been awarded by three Nobel prizes and appreciated by millions of ulcer patients all over the world.

4

Mucosal expression and luminal release of transforming growth factor [TGFalpha] and epidermal growth factor [EGF] in duodenal ulcer [DU] before and after eradication of Helicobacter pylori [Hp]

88%

Konturek P. C. , Bielanski W. , Bobrzynski A. , Hahn E. G. , Konturek S. J.

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nr 1

5

The pilot study of 3-month course of melatonin treatment of patients with nonalcoholic steatohepatitis: effect on plasma levels of liver enzymes, lipids and melatonin

76%

Gonciarz M. , Gonciarz Z. , Bielanski W. , Mularczyk A. , Konturek P. C. , Brzozowski T. , Konturek S. J.

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nr 6

6

Gastroprotection by pentoxyfilline against stress-induced gastric damage. Role of lipid peroxidation, antioxidizing enzymes and proinflammatory cytokines

75%

Kwiecien S. , Brzozowski T. , Konturek P. C. , Pawlik M. W. , Pawlik W. W. , Kwiecien N. , Konturek S. J.

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nr 2

EN

Impairment of blood perfusion in gastric mucosa results in the formation of erosions and ulcers. Nitric oxide (NO), produced via activity of NO-synthase (NOS), appears to be a one of major factors, involved in the regulation of the gastric blood flow (GBF). Inhibition of this enzyme by N-nitro-L-arginine (L-NNA) results in local decrease of NO production, reduces GBF and impairs gastric mucosal integrity, the effects that can be reversed by the pretreatment with L-arginine, the NOS substrate. However, little information is available regarding the contribution of reactive oxygen species (ROS)-induced lipid peroxidation and NO to the mechanism of gastric mucosal integrity. Therefore, the aim of our present study was to determine the action of pentoxyfilline (PTX), an inhibitor of tumor necrosis factor alpha (TNFalpha) with or without NOS inhibition by L-NNA administration in rats with water immersion and restraint stress (WRS)-induced gastric lesions . Experiments were carried out on 100 male Wistar rats. The gastric blood flow (GBF) was measured using laser Doppler flowmeter. The area of gastric lesions was determined by planimetry and the levels of proinflammatory cytokines (IL-1ß and TNFalpha) were measured by ELISA. Colorimetric assays were employed to determine gastric mucosal levels of lipid peroxidation products, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) and antioxidant enzymes including superoxide dismutase (SOD) activity, as well as tissue concentration of reduced glutathione (GSH). Administration of PTX significantly attenuated the gastric lesions, induced by 3.5 h of WRS and this was accompanied by the rise in the GBF and a significant decrease in plasma proinflammatory cytokines (IL-1ß and TNFalpha) levels, as well as the reduction of lipid peroxidation. Exposure of rats to WRS supressed the SOD and GSH activities and these effects were reversed by PTX. The protective and hyperemic effects of PTX, as well as an increase in mucosal SOD activity and GSH concentration were counteracted by pretreatment with L-NNA, but restored by the pretreatment with L-arginine, a NOS substrate. We conclude that PTX exerts beneficial, gastroprotective effect against WRS-induced gastric lesions due to enhancement in gastric microcirculation, possibly mediated by the enhanced NOS activity as well as local action of NO and by the attenuation of oxidative metabolism and generation proinflammatory cytokines.

7

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.

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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.

8

The photoperiod, circadian regulation and chronodisruption: the requisite interplay between the suprachiasmatic nuclei and the pineal and gut melatonin

63%

Reiter R. J. , Rosales-Corral S. , Coto-Montes A. , Boga J. A. , Tan D.-X. , Davis J. M. , Konturek P. C. , Konturek S. J. , Brzozowski T.

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nr 3

EN

The current scientific literature is replete with investigations providing information on the molecular mechanisms governing the regulation of circadian rhythms by neurons in the suprachiasmatic nucleus (SCN), the master circadian generator. Virtually every function in an organism changes in a highly regular manner during every 24-hour period. These rhythms are believed to be a consequence of the SCN, via neural and humoral means, regulating the intrinsic clocks that perhaps all cells in organisms possess. These rhythms optimize the functions of cells and thereby prevent or lower the incidence of pathologies. Since these cyclic events are essential for improved cellular physiology, it is imperative that the SCN provide the peripheral cellular oscillators with the appropriate time cues. Inasmuch as the 24-hour light:dark cycle is a primary input to the central circadian clock, it is obvious that disturbances in the photoperiodic environment, e.g., light exposure at night, would cause disruption in the function of the SCN which would then pass this inappropriate information to cells in the periphery. One circadian rhythm that transfers time of day information to the organism is the melatonin cycle which is always at low levels in the blood during the day and at high levels during darkness. With light exposure at night the amount of melatonin produced is compromised and this important rhythm is disturbed. Another important source of melatonin is the gastrointestinal tract (GIT) that also influences the circulating melatonin is the generation of this hormone by the entero-endocrine (EE) cells in the gut following ingestion of tryptophan-containing meal. The consequences of the altered melatonin cycle with the chronodisruption as well as the alterations of GIT melatonin that have been linked to a variety of pathologies, including those of the gastrointestinal tract.

9

Central and peripheral gastroprotective and secretory activity of histamine and its N-alpha methyl analog

63%

Brzozowski T. , Konturek P. C. , Pawlik M. , Kwiecien S. , Pajdo R. , Drozdowicz D. , Konturek S. J. , Hahn E. G.

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tom 52

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nr 2

10

One week treatment with omeprazole, clarithromycin and tinidazole or lansoprazole, amoxicillin and metronidazole for cure of Helicobacter pylori infection in duodenal ulcer patients

63%

Sito E. , Konturek P. C. , Bielanski W. , Kwiecien N. , Konturek S. J. , Baniukiewicz A. , Jedynak M. , Gabryelewicz A. , Hahn E. G.

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tom 47

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nr 1

11

Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, interacts with gastric oxidative metabolism and enhances stress-induced gastric lesions

51%

Kwiecien S. , Ptak-Bielowska A. , Krzysiek-Maczka G. , Targosz A. , Jasnos K. , Magierowski M. , Szczyrk U. , Brzozowski B. , Konturek S. J. , Konturek P. C. , Brzozowski T.

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nr 5