Cytoprotective Prostaglandins Research Articles

Rhodiola rosea L. extract ameliorates ethanol-induced gastric ulcer in rats by alleviating oxidative stress and inflammation via NF-κB pathway inhibition

Rhodiola rosea L. is a traditional plant that has been found to exhibit a wide range of biological activities, however, there is a lack of research regarding its potential anti-ulcer activity. In this study, the plant’s anti-ulcer activity has been evaluated in detail for the first time. R. rosea methanolic extract anti-ulcer activity was investigated against ethanol-induced ulcer rats. The results showed that administering the extract to ulcerated rats reduced gastric acidity and ulcer index while improving nitric oxide (NO) and cytoprotective prostaglandin E2 (PGE2), as well as anti-oxidants glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). On the other hand, the extract decreased malondialdehyde (MDA) and myeloperoxidase (MPO) levels. Further, ELISA assays showed that R. rosea extract decreased pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α levels in ulcerated rats. Western blot analysis confirmed the ELISA results, indicating that the extract decreased IL-6 and TNF-α protein expression and inhibited the NF-κB signalling pathway. Macroscopic and histological investigations on ulcerated rats verified the extract's anti-ulcer effects. The extract’s anti-ulcer activity was dose-dependent with the 600 mg/kg/day dose showing superior activity across all assays. GCMS analysis identified the extract’s major constituents as bicyclo [4.1.0] heptane, 7-pentyl (50.784 %) followed by 2-heptadecenal (33.2 %), and it is thought that these compounds play a crucial role in the extract’s bioactivity. Finally, in silico studies showed that the most abundant molecule, bicyclo [4.1.0] heptane, 7-pentyl, demonstrated the highest binding affinity in its interaction with H+, K+-ATPase. Taken together, the extract’s mode of action might include the inhibition of H+, K+-ATPase by bicyclo [4.1.0] heptane, 7-pentyl, followed by NF-κB pathway inhibition and subsequent regulation of cytokines and other inflammatory biomarkers. This innovative finding has the potential to lead to a successful anti-ulcer medicine, which might be followed by additional clinical trials or bioguided isolation research.

Tangeretin Protects against Ethanol‐Induced Injury in Gastric Mucosa of Rats via its Antioxidants and Anti‐inflammatory Activity

Tangeretin (TG), a polymethoxy citrus flavone, has attracted attention due to its significant antioxidant and anti‐inflammatory activities. It showed valuable pharmacological actions and protected against cancer, diabetic‐, liver‐ and renal‐induced injuries. However, its antiulcer activity has not been investigated.This study aimed to explore the possible protective effects of TG against ethanol‐induced gastric injury in rats. Adult male Wistar rats were used and divided into five groups: Control, TG, EtOH, EtOH+TG and EtOH+ Pantoprazole (PAN). Gastric injury was induced by a single dose of Absolute ethanol (5ml/Kg, p.0).Alcohol administration leads to significant macroscopic, histologic and biochemical gastric injuries. Treatment with TG (100mg/kg p.o.) protected against EtOH‐induced gastric injuries as demonstrated by the decrease in the ulcer and bleeding scores. Tangeretin boosted the antioxidants properties of the gastric mucosa via the inhibition of Malondialdehydes (MDA) and nitric oxides (NO) while improving glutathione (GSH), superoxide dismutase (SOD) and the nuclear factor erythroid 2–related factor 2 (Nrf2). Tangeretin curbed gastric inflammation by decreasing myeloperoxidase (MPO) and tumor necrosis factor‐α (TNF‐α) while increasing the anti‐inflammatory interleukin‐10 (IL‐10). In addition, TG caused the upregulation of the gastric cytoprotective prostaglandin E2 (PGE2). These results were comparable to those produced by PAN; the proton pump inhibitor.These findings reported for the first time the gastroprotective actions of TG in EtOH‐induced gastric injury which were mediated via suppression of inflammation and oxidative stress in addition to enhancing the antioxidant and the cytoprotective defenses.Support or Funding InformationThis work has been financially supported by the research grant# 2017‐A‐PH‐03 from the Deanship of Graduate Studies and Research, Ajman University.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Iloprost attenuates hyperoxia-mediated impairment of lung development in newborn mice.

Cyclooxygenase-2 (COX-2/PTGS2) mediates hyperoxia-induced impairment of lung development in newborn animals and is increased in the lungs of human infants with bronchopulmonary dysplasia (BPD). COX-2 catalyzes the production of cytoprotective prostaglandins, such as prostacyclin (PGI2), as well as proinflammatory mediators, such as thromboxane A2. Our objective was to determine whether iloprost, a synthetic analog of PGI2, would attenuate hyperoxia effects in the newborn mouse lung. To test this hypothesis, newborn C57BL/6 mice along with their dams were exposed to normoxia (21% O2) or hyperoxia (85% O2) from 4 to 14 days of age in combination with daily intraperitoneal injections of either iloprost 200 µg·kg-1·day-1, nimesulide (selective COX-2 antagonist) 100 mg·kg-1·day-1, or vehicle. Alveolar development was estimated by radial alveolar counts and mean linear intercepts. Lung function was determined on a flexiVent, and multiple cytokines and myeloperoxidase (MPO) were quantitated in lung homogenates. Lung vascular and microvascular morphometry was performed, and right ventricle/left ventricle ratios were determined. We determined that iloprost (but not nimesulide) administration attenuated hyperoxia-induced inhibition of alveolar development and microvascular density in newborn mice. Iloprost and nimesulide both attenuated hyperoxia-induced, increased lung resistance but did not improve lung compliance that was reduced by hyperoxia. Iloprost and nimesulide reduced hyperoxia-induced increases in MPO and some cytokines (IL-1β and TNF-α) but not others (IL-6 and KC/Gro). There were no changes in pulmonary arterial wall thickness or right ventricle/left ventricle ratios. We conclude that iloprost improves lung development and reduces lung inflammation in a newborn mouse model of BPD.

P114 Potassium competitive acid blocker, revaprazan, prevented indomethacin-induced intestinal permeability through tightening TJs

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs for arthritis, inflammation, and cardiovascular protection. However, they cause serious gastrointestinal side effects, of which pathophysiology has mostly been originated on the cyclooxygenase (COX) inhibition and the subsequent depletion of cytoprotective prostaglandin. Furthermore, recent clinical data showed that PPI aggravated NSAIDs-induced intestinal damages through either dysbiosis or increased intestinal permeability, suggesting PPI might be no more protective against NSAID-induced intestinal damages. In this study, we investigated the changes of indomethacin (IND)-induced small intestinal damages after combination with pantoprazole (PPZ) or combination with revaprazan (REV), potassium-competitive acid blocker (PCAB). All SD rats were 5 weeks of age. After treatment after 48 h rats with indomethacin in all the groups, they were euthanized and small intestine were collected for gross and pathologic evaluation, followed by immunohistochemical staining, Western blotting for inflammatory mediators, permeability protein, and RT-PCR As a result, macroscopic and histological evidences suggested that administration of IND resulted in significant intestinal damage and co-administration of PPZ resulted in worsen of IND enteropathy while attenuation of IND-induced intestinal damage in co-administration of REV. Moreover when we checked inflammatory cytokines and oxidative stress-associated factors using Western blotting and RT –PCR showed that IND with PPZ group was higher compared with IND alone group but IND plus REV group was lower compared with the PPZ group. Also we performed immunohistochemical staining to confirm intestinal permeability including ZO-1 and Occludin 1 as a result their expression was significantly decreased in IND with PPZ group, whereas no changes in IND + REV group, suggesting that PPZ aggravated IND-induced small intestinal damages, but not with REV combination. Thus this study in the near future that PCAB should be selected to secure NSAID-induced GI damages, while PPI should not be prescribed in this purpose.

Design, Synthesis and Biological Evaluation of New Thieno[2,3- d]pyrimidines as Anti-inflammatory Agents

Long term use of NSAIDS is mainly accompanied by major health implications such as gastrointestinal erosions, ulcerations and nephrotoxicity. These side effects arise from local irritation by the carboxylic acid moiety, that is common to most of NSAIDs (topical effect), in addition to decreased cytoprotective prostaglandin production. Therefore, in the medicinal chemistry research area, there is an ongoing need for the discovery of new, potent and safer anti-inflammatory lead compounds devoid of the irritant carboxylic acid moiety. A series of new 3-substituted-2-thioxo-thieno[2,3-d]pyrimidine derivatives were synthesized through reacting the starting 3-amino-2-thioxo-thieno[2,3-d]pyrimidines with different aromatic aldehydes. The structure of all newly synthesized compounds was confirmed with spectral and elemental analyses. The synthesized thieno[2,3-d]pyrimidines were investigated for in vivo anti-inflammatory activity, using the carrageenan induced paw edema test. The possible antiinflammatory mechanism was also evaluated by determining the concentration of prostaglandin E2 (PGE2) in blood serum using a rat specific PGE2 ELISA kit. All test compounds could significantly reduce carrageenan induced paw edema comparable to diclofenac sodium as a potent anti-inflammatory drug. Moreover, they could decrease the concentration of PGE2 in blood serum. Interestingly, compound 4c exhibited the most potent in vivo anti-inflammatory activity with protection of 35%, 36% and 42% against carrageenan-induced paw edema after 1h, 2h and 3h, representing 92%, 86% and 88% respectively of diclofenac activity. It also decreased the concentration of PGE2 in blood serum to 19 pg/ mL which is comparable to diclofenac with PGE2 concentration of 12 pg/ mL. Moreover, Compounds 4f, 4a, 4i and 4e exerted significant anti-inflammatory activity after 4h, representing 71%, 69%, 63% and 61% respectively of diclofenac activity. Furthermore, they significantly decreased the concentration of PGE2 in blood serum. These thienopyrimidines may be used as good candidates for the search of promising, potent and safe antiinflammatory leads for being free from acidic functions.

CLINICAL AND PHARMACOLOGICAL CHARACTERISTICS OF THE USE OF REBAMIPIDE IN DISEASES OF THE GASTROINTESTINAL TRACT LITERATURE REVIEW

NSAID-induced lesions of the gastrointestinal tract gained wide spread in the recent decade. Their range includes lesion of the esophagus, syndrome of dyspepsia, gastropathy and enteropathy. Diagnosis establishment of enteropathy is complicated and became possible after introduction of the capsule endoscopy. PPI are used for treatment of gastropathy, but they are not effective for treating enteropathy. Cytoprotective prostaglandins play the key role in the development of NSAID lesions of the gastrointestinal tract. Synthetic analogues of prostaglandins of misoprostol type possess cytoprotective action, but cause a significant number of adverse events. Rebamipide, a new gastroprotective agent in Russia stimulates production of endogenous prostaglandins. This drug proved its efficacy during the clinical trials performed according to the standards of the evidence-based medicine.

Diosmin protects against ethanol-induced gastric injury in rats: novel anti-ulcer actions.

Alcohol consumption has been commonly associated with gastric mucosal lesions including gastric ulcer. Diosmin (DIO) is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features that underlay its protection against cardiac, hepatic and renal injuries. However, its impact on gastric ulcer has not yet been elucidated. Thus, the current study aimed to investigate the potential protective effects of DIO against ethanol-induced gastric injury in rats. Pretreatment with DIO (100 mg/kg p.o.) attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of ulcer index (UI) scores, area of gastric lesions, histopathologic aberrations and leukocyte invasion. These actions were analogous to those exerted by the reference antiulcer sucralfate. DIO suppressed gastric inflammation by curbing of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) levels along with nuclear factor kappa B (NF-κB) p65 expression. It also augmented the anti-inflammatory interleukin-10 (IL-10) levels. Meanwhile, DIO halted gastric oxidative stress via inhibition of lipid peroxides with concomitant enhancement of glutathione (GSH), glutathione peroxidase (GPx) and the total antioxidant capacity (TAC). With respect to gastric mucosal apoptosis, DIO suppressed caspase-3 activity and cytochrome C (Cyt C) with enhancement of the anti-apoptotic B cell lymphoma-2 (Bcl-2) in favor of cell survival. These favorable actions were associated with upregulation of the gastric cytoprotective prostaglandin E2 (PGE2) and nitric oxide (NO). Together, these findings accentuate the gastroprotective actions of DIO in ethanol gastric injury which were mediated via concerted multi-pronged actions, including suppression of gastric inflammation, oxidative stress and apoptosis besides boosting of the antioxidant and the cytoprotective defenses.

Role of Phospholipids in Protection of the GI Mucosa

The focus of peptic ulcer disease research has evolved over the past 50 years. In the past, the greatest interest understandably has been in studying the regulation of gastric acid secretion, following the century-old Schwarz’s dictum of ‘‘no acid, no ulcer’’ [1]. As a consequence, understanding the regulation of gastric acid section and the potential causes of gastric acid hypersecretion became a central research focus until 1970, with major scientific advances including the elucidation of the role of gastrin, acetylcholine, and histamine as physiological stimulants of acid secretion and the identification of luminal acid and somatostatin as physiological inhibitors [2]. Afterwards, the emphasis was on the development of pharmacological inhibitors of gastric acid secretion, with the clinically important discovery of highly effective H2 receptor antagonists (H2RAs) followed by the even more efficacious proton pump inhibitors (PPIs) [3–7]. During this same period came the major discovery by Robert and associates of the role of prostaglandins in inhibiting gastric acid secretion, and more importantly in protecting the gastric mucosa from a damaging agents and ulcerogenic conditions (e.g., stress), a remarkable finding at the time, termed ‘‘cytoprotection’’ [8]. The multi-factorial mechanism that underlies prostaglandin’s cytoprotective action appears to involve increasing and/or maintaining tight junctional integrity, increasing intestinal mucus and bicarbonate section, and increasing mucosal hydrophobicity, mitochondrial integrity, and blood flow [9, 10]. The development of prostaglandins as clinical cytoprotective agents, however, has been disappointing due to the side-effect profile of these biologically active lipids to stimulate uterine and intestinal smooth muscle contraction and intestinal secretion, which may result in miscarriages, bloating, and diarrhea [11]. Lastly, the discovery of Helicobacter pylori by Marshall and Warren [12] revolutionized the field of peptic ulcer disease by implicating a micro-organism in its pathogenesis, leading to novel antibiotic combination therapeutic approaches which not only remarkably reduced the incidence of peptic ulcer disease but of gastric cancer as well [13, 14]. The mechanism by which H. pylori causes peptic ulcer disease surprisingly has yet to be fully resolved, but appears to be dependent on the gastric localization of the infection (antrum vs. body), gastric acid hypersecretion (mostly linked to antral infection), and defects in gastroduodenal barrier function [15, 16]. Nonsteroidal anti-inflammatory drugs (NSAIDs), which are regularly consumed by a large percentage of our populace, represent the other major cause of GI ulceration, with gastroduodenal erosions and/or ulcers affecting between 15 and 40 % of those regularly taking NSAIDs [17], and lower gut pathology being present in [50 % of chronic NSAID users [18]. The mechanism by which aspirin and related NSAIDs injure the GI mucosa was once thought to be strictly due to disruption of the biosynthesis of cytoprotective prostaglandins via inhibition of constitutive cyclooxygenase1 (COX-1) [19], leading to the development of highly selective COX-2 inhibitors (coxibs) as safer anti-inflammatory drugs. However, over time this concept has been challenged, with the demonstration that NSAIDs can induce GI injury by COX-independent mechanisms [20], and the demonstration that a number of highly selective coxibs have unanticipated and potentially L. M. Lichtenberger (&) Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, TX 77030, USA e-mail: lenard.m.lichtenberger@uth.tmc.edu

Antioxidant and gastric cytoprotective prostaglandins properties of Cassia sieberiana roots bark extract as an anti-ulcerogenic agent

BackgroundCassia sieberiana is a savannah tree with a wide phytotherapeutic application including the use of its roots in the management of various stomach disorders including gastric ulcer, stomach pains and indigestion. The aim of the study is to evaluate the antioxidant, gastric cytoprotective prostaglandins, secretory phospholipase A2, phytochemical and acute toxicity properties of Cassia sieberiana roots bark extract in a bid to justify its phytotherapeutic applications in gastric ulcer.MethodsAntioxidant and radical scavenging activities of the roots bark extract of Cassia sieberiana were assayed. Serum secretory phospholipase A2 (sPLA2) concentration and activity and the formation of gastric mucosal prostaglandins E2 (PGE2) and I2 (PGI2) were also assessed. Comparisons between means were performed using analysis of variance (ANOVA) followed by Students Standard Newman-Keuls post hoc analysis to determine statistical significance. P < 0.05 was considered significant.ResultsThe extract was found to possess significant ferric reducing antioxidant power and can scavenge hydroxyl radicals. The extract also possesses DPPH scavenging activity, can chelate ferrous ion and a dose-dependent protective effect against lipid peroxidation and free radical generation. Prostaglandin studies showed that the roots bark extract dose dependently increased gastric mucosal PGE2 and PGI2 levels and also decreased serum sPLA2 activity. Phytochemical analyses suggest that the roots extract contains polyhydroxyl/phenolic substances. Acute toxicity test showed no sign of toxicity up to a dose level of 2000 mg/kg body weight p.o.ConclusionsC. sieberiana roots extract possesses significant antioxidant and gastric cytoprotective prostaglandin properties as well as serum secretory phospholipase A2 inhibitory activity which could be due to its content of polyhydroxy and/or phenolic substances. This may justify its use as an anti-ulcerogenic agent in traditional medicine in West Africa.

ANTIULCER ACTIVITY OF THE METHANOLIC EXTRACT OF SESBANIA GRAINDIFLORA

The anti ulcerogenic activity of Sesbania graindiflora was evaluated by employing aspirin and pylorus ligation induced ulcerations in rats. Non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin are known to induce gastric ulceration. The reason being attributed principally to inhibition of biosynthesis of ‘cytoprotective prostaglandins’ (by inhibition of cyclo-oxygenase pathway of arachidonic acid metabolism), resulting in overproduction of leukotrienes and other products of 5-lipoxygenase pathway. Hence, the protective action of Sesbania graindiflora against aspirin- induced gastric lesions could possibly be due to its 5-lipoxygenase inhibitory effect.

Oxidative stress, nitric oxide and prostaglandin E2 levels in the gastrointestinal tract of aging rats

Abstract Objectives To evaluate the presence of oxidative stress and alterations in the levels of two cytoprotective agents, prostaglandin E2 and nitric oxide, in the gastrointestinal tract of aging rats. Methods The production of superoxide anion, lipid peroxides, levels of superoxide dismutase and catalase, and production of prostaglandin E2 and nitric oxide in the stomach and duodenum of rats were determined at 1.5, 3, 12, 18 and 24 months of age. Key findings Oxidative stress was present in the stomach of the old rats (24 months), whereas prostaglandin E2 and nitric oxide production remained stable at 18 and 24 months. In the duodenum, no oxidative stress was observed at 24 months, but at 18 months, an increase in superoxide anion levels was detected. Prostaglandin E2 remained constant in the aged rats but nitric oxide decreased significantly at 24 months. Conclusions The absence of macroscopic gastric injury throughout the gastrointestinal tract indicates that the oxidative stress in the stomach and the significant decrease of nitric oxide in the duodenum in the old rats are not sufficient to disrupt the mucosal defence network. The results support the notion that the disruption of the mucosal network is essentially regulated by the cytoprotective agents prostaglandin E2 and nitric oxide, and that injury appears only when both substances are concurrently reduced.

Emergent Aspirin Use in Cardiovascular Disease in the Emergency Department: Oral Dosing versus Rectal Suppositories

Emergent Aspirin Use in Cardiovascular Disease in the Emergency Department: Oral Dosing versus Rectal Suppositories

7β-hydroxy-epiandrosterone modulation of 15-deoxy-Δ 12,14-prostaglandin J 2, prostaglandin D 2 and prostaglandin E 2 production from human mononuclear cells

7β-hydroxy-epiandrosterone (7β-OH-EPIA) has been shown to be cytoprotective in various organs including the brain. It has also been shown that prostaglandin D 2 (PGD 2) and its spontaneous metabolite 15-deoxy-Δ 12,14-prostaglandin J 2 (15d-PGJ 2) are also cytoprotective. It is possible that these prostaglandins derived from circulating mononuclear cells may mediate the actions of 7β-OH-EPIA. The aim of this study, therefore, was to ascertain the effect of 7β-OH-EPIA (in the absence or presence of tumour necrosis factor-α (TNF-α)), a pro-inflammatory stimulus, on the biosynthesis of PGD 2, PGE 2 and 15d-PGJ 2 from human mononuclear cells. Prostaglandins were measured by enzyme immunoassay (EIA). 7β-OH-EPIA alone induced a concentration-dependant increase in the production of PGD 2. TNF-α increased PGD 2 levels which were enhanced by 7β-OH-EPIA. 7β-OH-EPIA increased 15d-PGJ 2 levels both in the absence and presence of TNF-α. 7β-OH-EPIA alone had no effect on PGE 2 biosynthesis but suppressed TNF-α-induced PGE 2 circa 50%. 7β-OH-EPIA also increased the level of free arachidonic acid and radiolabelled prostaglandins in cells pre-incubated with radiolabelled arachidonic acid, indicating that the increase may occur via the enhanced release of substrate arachidonic acid. 7β-OH-EPIA did not affect levels of the anti-inflammatory cytokine IL-10 indicating that this is an unlikely mechanism by which 7β-OH-EPIA induces its actions but more likely exerts its effects via the production of cytoprotective prostaglandins.

The gastric ulcer protective effect of boswellic acids, a leukotriene inhibitor from Boswellia serrata, in rats

Aim of the study is to evaluate the anti-ulcer efficacy of the boswellic acids (BA), a triterpenoid known as anti-inflammatory/anti-arthritic agent, which is in clinical use. The reason for the study is that, the known non-steroidal anti-inflammatory drugs (NSAIDs) are full of side effects especially ulceration which is at the top. BA, although, used as an anti-arthritic agent yet it is not only devoid of ulcer production but protective also. The activity evaluation was done by the following universally accepted animal models viz., pyloric ligation, ethanol-HCl, acetylsalicylic acid, indomethacin and cold restrained stress-induced ulceration in rats. Results of the present study revealed that BA possess a dose dependent antiulcer effect against different experimental models. It showed different degree of inhibition of the ulcer score towards different ulcerogenic agents. The ulcer score against various ulcer inducing agents viz., pyloric ligation, ethanol/HCl, (acute and chronic) acetylsalicylic acid, indomethacin and cold restraint stress, was inhibited by 39%, 38%, 51%, 31%, 37% and 42% respectively at 250mg/kg. From the data it is concluded that BA inhibited ulcer production non-specifically in all the experimental models, whereby, it is not possible to propose a single specific mechanism. Nevertheless it is possible that BA might be acting by increasing the gastric mucosal resistance and local synthesis of cytoprotective prostaglandins and inhibiting the leukotriene synthesis.

Gaultherin, a natural salicylate derivative from Gaultheria yunnanensis: Towards a better non-steroidal anti-inflammatory drug

One of the major factors limiting the use of non-steroidal anti-inflammatory drugs is gastrointestinal toxicity. Gaultherin, 2-[(6-O-β- d-Xylopyranosyl-β- d-glucopyranosyl)oxy] benzoic acid methyl ester, a natural salicylate derivative extracted from Gaultheria yunnanensis, has been shown to have analgesic and anti-inflammatory effects and lack gastric ulcerogenic effect compared to aspirin in our primary study. The aim of this study was to investigate the mechanism of action of gaultherin, which may rely on its active metabolite, and the mechanism responsible for the non-ulcerogenic property. The results showed that gaultherin (200 mg/kg) significantly inhibited the abdominal contractions in the acetic acid-induced writhing test in mice. The anti-inflammatory effect of gaultherin was demonstrated in the croton oil-induced ear edema model in mice. The results showed that gaultherin and equimolar dose of aspirin produced comparable inhibitory effects. The study of the metabolism characters of gaultherin in mice and rats indicated that gaultherin could be metabolically converted to salicylate, which produced the pharmacological effects, and provided effective concentrations for an extended period. In vitro metabolism experiment showed that gaultherin was metabolized by β-glycosidase produced by human intestinal bacteria and esterases in intestine, blood and liver successively to release salicylate finally. The study suggested gaultherin did not cause gastric ulcer for the reason that it released salicylate in intestine slowly, not in stomach and it left the cyclooxygenase-1 unaffected, which was the source of cytoprotective prostaglandins in gastric epithelium.

A mechanism for prostaglandin cytoprotection.

Topical 16,16-dimethyl (dm) prostaglandin E2 produces an alkaline secretion from the canine stomach. This study attempts to assess whether this prostaglandin-induced secretion might have a cytoprotective role. Chambered ex vivo perfused wedges of canine stomach were divided into equal halves: a control and test side. The mucosa of each half was sequentially exposed to isosmotic hydrochloric acid, 20 microgram of 16,16 dm PGE2 in acid, 20 mmol aspirin + 20 microgram of dm PGE2 in acid then isosmotic acid. The test side received 40 mmHg pneumatic counterpressure to reduce the prostaglandin-induced fluid movement before, during and after the aspirin exposure. The mucosal lesions produced on each side were graded 0 to 14. If prostaglandin exerts its cytoprotective effect by stimulating an alkaline secretion, elimination of that secretion with counterpressure should prevent a cytoprotective action. Nine dogs were studied. Topical prostaglandin increased transmucosal fluid movement from 10 microliter/min to 65 microliter/min. Counterpressure decreased this volume flow by 50 per cent (P < 0.01); it also decreased mucosal blood flow on the test side by 20 per cent (P < 0.05). The lesions on the counterpressure side were worse 2.0 +/- 0.6 v. 0.8 +/- 0.3 (P < 0.01). Thus the greater damage in the counterpressure group could have been caused by diminished fluid movement or by reduced blood flow or a combination of both factors. Although this study cannot distinguish between these possibilities, it seems like that the prostaglandin-induced alkaline secretion has a cytoprotective role.

Effect of H. pylori infection on the expression of cyclooxygenase-2 in human gastric mucosa

Cyclooxygenase-1 is the primary isoform responsible for the production of cytoprotective prostaglandins (PGE 2 and PGI 2) in the stomach. In contrast COX-2 is induced at the sites of inflammation. Using Helicobacter pylori infection as a model of inflammation, this study was designed to evaluate the effects of H. pylori infection on prostanoid synthesis and expression of COX-2 in human gastric mucosa. Prostaglandin (PGE 2) and prostacyclin (PGI 2) synthesis in gastric biopsies obtained from 21 patients undergoing diagnostic endoscopy, were determined. H. pylori was detected by CLO test, histology and culture. Biopsy samples were incubated either with NS-398, selective COX-2 inhibitor or aspirin. Samples were also treated with endotoxin (LPS) in order to induce COX-2 expression. Tissue was also analysed for COX-2 expression in vivo by immunohistochemistry. In 15 out of 21 patients, H. pylori was detected by at least two of the three methods. Higher levels of PGE 2 and PGI 2 were seen in patients infected with H. pylori (191±30 and 245±88 ng/mg protein, respectively) compared with non-infected patients (77±17 and 120±36 ng/mg protein, respectively). There was significant inhibition of PGE 2 and PGI 2 with aspirin in both H. pylori infected (28±6.6 and 53±43 ng/mg, respectively) and in non-infected patients (16±7 and 12.5±3.5 ng/mg protein, respectively). However, NS-398 and LPS did not alter prostaglandin function significantly. Immunohistochemistry in all patients irrespective of Hp status demonstrated expression of COX-2. Lower concentration of constitutive expression of COX-2 was detected in human gastric mucosa by immunohistochemistry, however, H. pylori infection failed to induce COX-2 protein. In addition, increased prostaglandin synthesis in Hp-infected patients appears to be COX-1 mediated rather than COX-2. Furthermore, failure of endotoxaemia-treated sample to produce more PGE 2 in the face of enhanced COX-2 expression in gastric mucosa further suggests that increased prostanoids in human gastric stomach are COX-1 mediated.

Epidemiological and Clinical Aspects of Nonsteroidal Anti-inflammatory Drugs and Cancer Risks

It is well known that about 70% of cancer cases are due to environmental, dietary, or lifestyle factors. Accordingly, these cases maybe avoided by appropriate modifications. In addition, active chemoprevention has become a major interventional approach following the epidemiological observation of a beneficial effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in colon cancer prevention. This is chiefly due to the inhibition of the cyclooxygenase (COX) enzymes. The COX enzymatic system includes two isoenzymes, COX-1 and COX-2, that convert arachidonic acid to prostaglandins. COX-1 is constitutively expressed and synthesizes cytoprotective prostaglandins in the gastrointestinal tract. COX-2 is inducible by the oncogenes ras and scr and other cytokines; it is overexpressed in human cancer cells in which it stimulates cellular division and angiogenesis and inhibits apoptosis. NSAIDs restore apoptosis and decrease tumor mitogenesis and angiogenesis. Most cancer cells have been found to exhibit overexpression of COX-2. Epidemiological studies showed a lower risk of developing cancer of the colon, breast, esophagus, and stomach following the ingestion of NSAIDs. The use of NSAIDs in low dose was associated with a statistically significant decrease in the risk of adenomatous polyps and of overt colon cancer. The regressive effects of sulindac on foci of aberrant crypts in the colon (considered to be precursors of adenoma), and on adenocarcinoma of the colon, are of particular interest because this NSAID does not have an inhibitory effect on COX. This may support the view that the antineoplastic effect of NSAIDs may also be due to a mechanism other than COX-2 inhibition. In breast cancer, large cohort studies reported a 40 to 50% reduced risk of developing cancer, a smaller size of the primary tumor, and a reduction in the number of involved axillary lymph nodes. Similar findings have been reported in the esophagus and stomach, but not in gastric cardia adenocarcinoma. The recent development of selective COX-2 inhibitors resulted in better clinical tolerance than that associated with NSAIDs in general, with the absence of gastrointestinal side effects known to occur after the inhibition of COX-1. Encouraging results have been obtained with these new agents in familial adenomatous polyposis, colon, breast, and prostate cancer.

Pathogenesis of inflammatory bowel disease

In spite of expanding knowledge of cellular and molecular mechanisms of intestinal inflammation, the etiology and pathogenesis of inflammatory bowel disease (IBD) remain obscure. The link between the environment and IBD is still circumstantial, but definite progress is occurring in defining genetic susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC). The notion that normal enteric flora play a role in initiating or maintaining IBD is gaining momentum. Some components of the flora may act as noxious agents, whereas others (probiotics) seem to have a protective effect. The importance of the mucosal immune system to IBD is established, and evidence is accumulating that nonimmune components, such as epithelial, mesenchymal, and endothelial cells, also contribute to gut inflammation. The effect of cytokines in intestinal immunity is being elucidated by studies on their molecular mechanism, particularly the activation of nuclear factor (NF)-kappaB. Finally, the beneficial effects of cytoprotective prostaglandins and cell adhesion molecule (CAM) blockade promise novel therapeutic opportunities derived from an improved understanding of IBD pathogenesis.

Discovery of a new class of selective cyclooxygenase-2 (COX-2) inhibitor that covalently modifies the isozyme.

Prostaglandin endoperoxide synthase (PGHS) catalyzes the first two steps of the arachidonic acid cascade leading to prostaglandin and thromboxane biosynthesis.1 Two distinct PGHS isozymes exist in mammals.2 PGHS-1 is constitutively expressed and involved in the synthesis of cytoprotective prostaglandins in the stomach and thromboxanes in platelets, whereas PGHS-2 is inducible and is a major contributor to prostaglandin biosynthesis in inflammatory cells and in the brain.3 The differential tissue distribution of the isozymes provides a basis for the development of selective PGHS-2 or COX-2 inhibitors as antiinflammatory and analgesic agents without the gastrointestinal and vascular liabilities that plague all currently available NSAIDs. Most COX-2 inhibitors developed to date, including the diarylheterocycles4 and the acidic sulfonamides5, inhibit the enzyme by binding tightly but noncovalently at the cyclooxygenase active site.6 KeywordsArachidonic Acid CascadeProstaglandin EndoperoxideCovalent ModifierColon Cancer Cell GrowthActive Site Serine ResidueThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.