Aneta Targosz

Agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ: A new compound with potent gastroprotective and ulcer healing properties

Pioglitazone, a specific ligand for peroxisome proliferator-activated receptor gamma (PPAR-γ), was recently implicated in the control of inflammatory processes and in the modulation of the expression of various cytokines such as tumor necrosis factor alpha (TNF-α), but its role in the mechanism of gastric mucosal integrity has not been studied extensively. This study was designed to determine the effect of pioglitazone on gastric mucosal lesions induced in rats by topical application of 100% ethanol and by 3.5 h of water immersion and restraint stress (WRS) with or without pretreatment with indomethacin (5 mg/kg i.p.) to inhibit cyclooxygenase-1 (COX-1) and COX-2 enzyme activities and L-NNA (20 mg/kg i.p.) to suppress nitric oxide (NO)-synthase. In addition, the effect of pioglitazone on ulcer healing in rats with chronic acetic acid ulcers (ulcer area 28 mm2) was determined. Rats were killed 1 h and 3.5 h after ethanol administration or WRS exposure or at day 9 upon ulcer induction, and the number and area of gastric lesions were measured by planimetry, the gastric blood flow (GBF) was determined by H2-gas clearance technique and the mucosal PGE2 generation and gene expression and plasma concentration of TNF-α and IL-1β were also evaluated. Pre-treatment with pioglitazone dose-dependently attenuated gastric lesions induced by 100% ethanol and WRS; the dose reducing these lesions by 50% (ID50) being 10 mg/kg and 7 mg/kg, respectively. The protective effect of pioglitazone was accompanied by the significant rise in the GBF, an increase in PGE2 generation and the significant fall in the plasma TNF-α and IL-1β levels. Strong signals for IL-1β-and TNF-α mRNA were recorded in gastric mucosa exposed to ethanol or WRS, and these effects were significantly decreased by pioglitazone. Indomethacin which suppressed PG generation by about 90%, while augmenting WRS damage, and L-NNA, that suppressed NO-synthase activity, significantly attenuated the protective and hyperaemic activity of this PPAR-γ ligand. In the chronic study, pioglitazone significantly reduced the area of gastric ulcers on day 9 and significantly raised the GBF at the ulcer margin. The acceleration of ulcer healing by PPAR-γ ligand was accompanied by a significant increase in the expression of PECAM-1 protein, a marker of angiogenesis. We conclude that (1) pioglitazone exerts a potent gastroprotective and hyperaemic actions on the stomach involving endogenous PG and NO and attenuation of the expression and release of proinflammatory cytokines TNF-α and IL-1β, and (2) PPAR-γ ligand accelerates ulcer healing, possibly due to the enhancement in angiogenesis at ulcer margin.

Nitric oxide-releasing aspirin but not conventional aspirin improves healing of experimental colitis

AIM To determine the effect of non-selective cyclooxygenase (COX) inhibitors, selective COX-2 inhibitors and nitric oxide (NO)-releasing aspirin in the healing of ulcerative colitis. METHODS Rats with 2,4,6 trinitrobenzenesulfon-ic acid (TNBS)-induced colitis received intragastric (ig) treatment with vehicle, aspirin (ASA) (a non-selective COX inhibitor), celecoxib (a selective COX-2 inhibitor) or NO-releasing ASA for a period of ten days. The area of colonic lesions, colonic blood flow (CBF), myeloperoxidase (MPO) activity and expression of proinflammatory markers COX-2, inducible form of nitric oxide synthase (iNOS), IL-1β and tumor necrosis factor (TNF)-α were assessed. The effects of glyceryl trinitrate (GTN), a NO donor, and 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-​tetramethyl-1H-imidazolyl-1-oxy-3-oxide, onopotassium salt (carboxy-PTIO), a NO scavenger, administered without and with ASA or NO-ASA, and the involvement of capsaicin-sensitive afferent nerves in the mechanism of healing the experimental colitis was also determined. RESULTS Rats with colitis developed macroscopic and microscopic colonic lesions accompanied by a significant decrease in the CBF, a significant rise in colonic weight, MPO activity and plasma IL-1β and TNF-α levels. These effects were aggravated by ASA and 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560), but not celecoxib and counteracted by concurrent treatment with a synthetic prostaglandin E₂ (PGE₂) analog. Treatment with NO-ASA dose-dependently accelerated colonic healing followed by a rise in plasma NO(x) content and CBF, suppression of MPO and downregulation of COX-2, iNOS, IL-1β and TNF-α mRNAs. Treatment with GTN, the NO donor, significantly inhibited the ASA-induced colonic lesions and increased CBF, while carboxy-PTIO or capsaicin-denervation counteracted the NO-ASA-induced improvement of colonic healing and the accompanying increase in the CBF. These effects were restored by co-treatment with calcitonin gene related peptide (CGRP) and NO-ASA in capsaicin-denervated animals. CONCLUSION NO-releasing ASA, in contrast to ASA, COX-1 inhibitors, and SC-560, accelerated the healing of colitis via a mechanism involving NO mediated improvement of microcirculation and activation of sensory nerves releasing CGRP.

Lipoxins, The Novel Mediators of Gastroprotection and Gastric Adaptation to Ulcerogenic action of Aspirin

Previous studies revealed that prostaglandins contribute to the mechanism of maintenance of gastrointestinal integrity and mediate various physiological aspects of mucosal defense. The suppression of prostaglandin synthesis in the stomach is a critical event in terms of the development of mucosal injury after administration of various NSAID including aspirin (ASA). A worldwide use of ASA is now accepted due to its remarkable analgesic, antipyretic and anti-thrombotic prophylactics against myocardial infarct and coronary disorders despite the fact that the use of NSAIDs is associated with the risk of gastrointestinal bleedings, haemorrhagic lesions and ulcerations. It has become clear that other mediators besides prostaglandins can similarly act to protect the gastrointestinal mucosa of experimental animals and humans from injury induced by ASA. For instance, nitric oxide (NO) released from vascular epithelium, epithelial cells of gastrointestinal tract and sensory nerves can influence many of the same components of mucosal defense as do prostaglandins. This review was designed to provide an updated overview based on the experimental and clinical evidence on the involvement COX-2 derived products, lipoxins in the mechanism of gastric defense, gastroprotection and gastric adaptation to ASA. Lipoxins were recently considered as another group of lipid mediators that can protect the stomach similarly as NO-donors known to exert protective influence on the stomach from the injury under condition where the mucosal prostaglandin levels are suppressed. The new class of NO-releasing NSAIDs, including NO-aspirin or NO-naproxen, represent a very promising approach to reducing the toxicity of their parent NSAIDs. Aspirin-triggered lipoxin (ATL) synthesis, via COX-2, acts to reduce the severity of damage induced by this NSAID. Lipoxin analogues may prove to be useful for preventing mucosal injury and for modulating mucosal inflammation. Evidence presented in this review documents that ATL also play in important role in gastric adaptation during chronic ASA administration. Suppression of COX-2 activity by selective COX-2 inhibitors such as rofecoxib or celecoxib was shown to abolish the production of ATL and to diminish the gastric tolerability of ASA and gastric adaptation developed in response to repetitive administration of this NSAID. Synthetic analogues of lipoxins as well as newer class of NSAIDs releasing NO may be used in the future as the therapeutic approach to counteract adverse effects in the stomach associated with NSAIDs ingestion.

Role of Helicobacter pylori infection in cancer-associated fibroblast-induced epithelial-mesenchymal transition in vitro

Major human gastrointestinal pathogen Helicobacter pylori (H. pylori) colonizes the gastric mucosa causing inflammation and severe complications including cancer, but the involvement of fibroblasts in the pathogenesis of these disorders in H. pylori‐infected stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts. Their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue; however, the interaction between H. pylori and fibroblasts remains unknown. We determined the effect of coincubation of normal rat gastric fibroblasts with alive H. pylori (cagA+vacA+) and H. pylori (cagA−vacA−) strains on the differentiation of these fibroblasts into cells possessing characteristics of cancer‐associated fibroblasts (CAFs) able to induce epithelial‐mesenchymal transition (EMT) of normal rat gastric epithelial cells (RGM‐1).

Exploiting Significance of Physical Exercise in Prevention of Gastrointestinal Disorders

BACKGROUND Physical activity can be involved in the prevention of gastrointestinal (GI)-tract diseases, however, the results regarding the volume and the intensity of exercise considered as beneficial for protection of gastrointestinal organs are conflicting. AIMS AND METHODS The main objective of this review is to provide a comprehensive and updated overview on the beneficial and harmful effects of physical activity on the gastrointestinal tract. We attempted to discuss recent evidence regarding the association between different modes and intensity levels of exercise and physiological functions of the gut and gut pathology. RESULTS The regular, moderate exercise can exert a beneficial effect on GI-tract disorders such as reflux esophagitis, peptic ulcers, cholelithiasis, constipation and Inflammatory Bowel Disease (IBD) leading to the attenuation of the symptoms. This voluntary exercise has been shown to reduce the risk of colorectal cancer. On the other hand, there is considerable evidence that the high-intensity training or prolonged endurance training can exert a negative influence on GI-tract resulting in the exacerbation of symptoms. CONCLUSION Physical activity can exhibit a beneficial effect on a variety of gastrointestinal diseases, however, this effect depends upon the exercise mode, duration and intensity. The accumulated evidence indicate that management of gastrointestinal problems and their relief by the exercise seems to be complicated and require adjustments of physical activity training, dietary measures and medical monitoring of symptoms. More experimental and clinical studies on the effects of physical activity on GI-tract disorders are warranted. Especially, the association between the exercise intensity and data addressing the underlying mechanism(s) of the exercise as the complementary therapy in the treatment of gastrointestinal disorders, require further determination in animal models and humans.

Can Drinking Water Serve as a Potential Reservoir of Helicobacter pylori? Evidence for Water Contamination by Helicobacter pylori

Although the natural niche for H. pylori is the human stomach, for widespread infection to occur the organism may need to survive in the external environment [1]. Documented evidence relating to the survival of H.pylori outside the gastric niche is extremely limited. However, there are no established culture methods for the detection of viable H. pylori in the environment, in particular drinking water supplies, preventing the development of true epidemiological and risk assessments [2]. A number of drinking water studies have identified H. pylori in water preand post-chlorination [3]. Baker and colleague [4] found that H. pylori were more resistant to low levels of free chlorine than E. coli or C. jejuni. Moreno and colleagues [5] have shown that H. pylori could survive disinfection procedures that are normally used in drinking water treatment when bacterium H. pylori was found in the viable but not-culturable (VBNC) state. However, they did find that culture of H. pylori was lost after 5 min in water despite free chlorine levels of 0.96 mg/2l of water. Children born into high-income families supplied with municipal water are considered 12 times more likely to become colonized with H. pylori than those supplied from community wells. This suggests that municipal water is a possible risk factor in the transmission and acquisition of H. pylori. It is plausible to suggest that breaks in municipal pipes allow for infiltration of contaminated surface water [6].

The level of leptin in blood among patients with infective diarrhea

Wprowadzenie: Biegunka infekcyjna jest zespołem chorobowym, który charakteryzuje się wystąpieniem licznych stolców lub stolców ze zwiększoną ilością wody powstających na skutek zadziałania czynnika zakaźnego. Leptynę zalicza się do rodziny helikalnych cytokin klasy I, a jej wydzielanie zależy od wielkości tkanki tłuszczowej. Wzrost ilości zgromadzonej tkanki tłuszczowej powoduje nasilenie wydzielania tego związku hamującego ośrodek sytości. Stężenie leptyny zwiększa się po posiłku i zmniejsza kilka godzin po nim. Jej wytwarzanie nasilają niektóre cytokiny, a sama wpływa na komórki układu immunologicznego. Cel: Porównanie stężenia leptyny we krwi chorych na biegunkę infekcyjną na początku objawów oraz po wyleczeniu, 8 tyg. później, a także ocena korelacji stężenia tej cytokiny ze wskaźnikami biochemicznymi krwi chorych. Materiał i metody: Badania prospektywne przeprowadzono w grupie 30 chorych. Oznaczano im morfologię krwi obwodowej, stężenie białka C-reaktywnego (C-reactive protein – CRP) i leptyny w surowicy metodą ELISA. Wyniki: Stwierdzono różnice w stężeniach leptyny – większe jej stężenie w okresie biegunki infekcyjnej niż w okresie zdrowia, ale różnice te nie były istotne statystycznie. U chorych z biegunką infekcyjną odnotowano istotną zależność między liczbą płytek krwi, leukocytów i stężeniem CRP a stężeniem leptyny. Wnioski: Wyniki te wskazują na korelację, jaka istnieje między aktywnością stanu zapalnego, wyrażoną poziomem wskaźników zapalnych, i stężeniem cytokin prozapalnych a stężeniem leptyny u chorych z biegunką infekcyjną. Abstract