Morphometric evaluation of the effect of opioid peptides on cysteamine-induced ulcer in rats

Morphometry was used to study the action of an enkephalin analog and beta-endorphine on the duodenal mucosa in rats with an experimental ulcer induced by cysteamine. Enkephalin produced a more powerful protective action than endorphine. The antiulcerous action was manifested in the diminution of dystrophic changes, redistribution of inflamed cells with an increase in the lymphocyte and monocyte counts, and in the reduction of the number of tissue macrophages and histocytes. Administration of opioids provoked a particularly marked increase in the eosinophil count in the duodenal mucosa. All these effects were abolished by naloxone. It is concluded that the tissue effects of opioids are mediated by specific opiate receptors.     

胃溃疡对大鼠胃中HAP1表达的影响

建立冰乙酸性大鼠胃溃疡模型,采用ABC法进行免疫组织化学染色,观察并探讨胃溃疡对胃壁中HAP1(huntingtin as-soc iated protein 1,HAP1)表达的影响。结果溃疡组大鼠胃壁中HAP1阳性细胞数目及光密度与正常进食的大鼠相比显著增多。     

Role of bone marrow derived-mesenchymal stem cells against gastric ulceration: Histological,immunohistochemical and ultrastructural study

The current study aimed to assess the antiulcerogenic impact of mesenchymal bone marrow stem cells (BMMSCs) against gastric ulcer induced by the use of piroxicam in rats and to compare this effect with the antiulcer drug “Pantoloc ®” proton pump inhibitors. The study included histological, histochemical, immunohistochemical and ultrastructural examination in stomach of rats in different study groups. In the ulcerated group, the glandular region of the stomach displayed clear mucosal lesions occurring as perforations along the stomach axis. In addition, stomach displayed degeneration of surface mucous cells accompanied by pyknosis, vacuolation among parietal cells in ishmus region, basal region with vacuolated chief cells and karyolitic nucleus of parietal cells. Moreover, Stomach sections of ulcer model rats showed intensive immunoreactivity to cytokeratin 20, Cox 2 and PCNA. Findings of the present study have shown that BMMSCs have an ameliorative effect against piroxicam-induced gastric ulcer in rats. Collectively, the proposed work has shown that BMMSCs have a curative capacity as an antiulcer due to their high antioxidant activity. Further studies are required in molecular levels to understand the mechanism of action during treatment.     

Dynamics of DNA synthesis in the gastric mucosa in ulcer

Anomalous DNA synthesis was seen in the stomach mucosa of mice with experimental stomach ulcer during different phases of the ulcerous process, using histoautoradiography. At the early stage of ulcer formation a decrease in the label index (LI) is seen. Formation of the ulcer, morphologically similar to the shronic one, is accompanied by growth of the number of DNA-synthesizing cells in its margins. Over a period of ulcer healing proliferative activity of epithelium decreases approximately to an initial level. Histoautoradiographic studies of bioptates of the stomach mucosa obtained under spot gastroscopy in patients suffering from the ulcerous disease allowed to reveal intensifying proliferative activity of epithelium in the ulcer margins. Similar changes in LI were found in gastritis, followed by the gland affection, and in atrophic gastritis.     

EFFECTS OF CHRONIC STEROID INGESTION ON GASTRODUODENAL EPITHELIAL RENEWAL IN THE RAT

Steroids may predispose to peptic ulcer formation. One possible mechanism could be via alteration of normal epithelial renewal. to study the effects of steroids on gastroduodenal epithelial renewal, rats received hydrocortisone sodium succinate in the drinking water to deliver a dose of 10 mg/kg per day. Control rats received plain water. After 4 weeks, the rats were injected intraperitoneally with tritiated thymidine, to label proliferating cells, and killed 1 hr later, to determine measurements of epithelial proliferation, or 24 hr later to determine measurements of epithelial migration. Sections of fundus, antrum and post-pyloric duodenum were processed for light microscopy and autoradiography. In fundic and antral mucosa, steroid treatment resulted in a reduction in the number of labelled cells and in the size of the proliferative zone and, in the fundus, the mucosal thickness was reduced. In the duodenum, although the number of labelled cells remained unchanged, steroid treatment did decrease the number of cells in the proliferative zone; further, crypt depth was reduced in steroid-treated rats, but villous height was increased, resulting in an overall increase in mucosal thickness. Epithelial migration was also depressed in fundic and antral mucosa, but appeared to be accelerated in the duodenum of steroid-treated rats. These studies indicate that although, in the duodenum, the effects of steroids on epithelial renewal are complex, in the stomach chronic steroid ingestion depresses epithelial renewal both in fundic and antral mucosa. This inhibition of epithelial renewal in the stomach may contribute to the ulcerogenic action of steroids by either rendering the mucosa susceptible to the effects of other ulcerogens or by retarding the healing of existing mucosal lesions.     

Certain Mechanisms regulating cell renewal in the gastric mucosa in peptic ulcer

A study was made of the effect of an aqueous extract of human gastric mucosa on the mitotic activity of the surface epithelium of the mouse stomach. The extract was found to exert a statistically significant inhibitory action. An extract from the mucosa of the stomach resected for duodenal ulcer exerted a more pronounced inhibitory action as compared with an extract from the stomach resected for gastric ulcer. This fact may be accounted for by a greater content of mature differentiated cells in duodenal ulcer. Tissue-specific action of gastric chalone is indicated by the absence of mitotic inhibition in the small intestinal mucosa.     

Brain blood supply and beta-endorphin and corticotropin content on exposure to thyroliberin

Thyroliberin produces a marked depressant action on the reflex cerebrovascular constriction reactions. The lack of changes in the content of immunoreactive beta-endorphine in blood and CSF indicates that apparently the cerebrovascular effects of the drug are not mediated via the opioid system but are due to a direct influence of thyroliberin on the central mechanisms by which brain circulation is regulated. Thyroliberin increases the blood corticotropin content, which causes an elevation of the arterial blood pressure and cerebrovascular tension. On the contrary, in the CSF the corticotropin level decreases after thyroliberin administration. The data obtained show that there is no correlation between the content of beta-endorphine and corticotropin in blood and CSF under the action of thyroliberin.     

Mechanism of the antiulcerogenic effect of IL-11 on acetic acid-induced gastric ulcer in rats

The purpose of this study was to evaluate the healing effect of interleukin-11 (IL-11) on acetic acid-induced gastric ulcer in rats. Gastric ulcers were induced in male Wistar rats by applying acetic acid to the fundus of the stomach. Recombinant human interleukin-11 (rhIL-11 100 microg/kg/twice daily, subcutaneously) was administered starting on the 2nd day before ulcer induction up through the 7th day after ulcer induction. Control rats were injected with bovine serum albumin. At 12 hours and 7 days after ulcer induction, the animals were sacrificed, and the ulcer index, proliferating cell nuclear antigen (PCNA) expression, and IL-11alpha receptor expression in the gastric tissues were studied. The ulcer index of the rhIL-11-treated rats was significantly lower than that of the control rats at the 7th day. The expression of PCNA as evaluated by Western blotting and immunohistochemistry, was enhanced in both the mucosal proliferative zone and proper muscle layer of the rhIL-11-treated rats in comparison with that in the control rats. IL-11alpha receptor expression was observed in the mucosal neck cells of the rhIL-11-treated rats and control rats. These findings suggest that IL-11 accelerates ulcer healing by inducing the proliferation of mucosal and muscular cells.     

Serotonin excess in the brain modifies the effect of beta-endorphin and dalargin on the processes of learning and memory]

In experiments on outbred female rats the influence was studied and compared of two representatives of endogenous opioids beta-endorphine and the analogue of leu-enkephalin dalargin on the processes of learning and memory in normal conditions and at the change of functional state of serotoninergic system of the brain. Parallel, the influence was studied of neuropeptides on the content of serotonin (5-OT) and its metabolite--5-oxyindolacetic acid in various areas of the brain in control and at the 5-OT redundancy. Conditioned reflexes (CRs) were used of two-way avoidance and defensive CRs. It has been established that administration of neuropeptides to intact animals influences in different directions the elaboration of the CR of two-way avoidance and maze defensive CR, but also worsens their preservation. Redundancy of 5-OT in the brain modifies behavioural effects of beta-endorphine and dalargin manifested in appearance of new effect and elimination and change of direction of the effects observed in the intact animals. Redundancy of 5-OT in the brain changes metabolic effects of beta-endorphine and particularly of dalargin. The obtained data testify to a dependence of the effects of beta-endorphine and dalargin on the functional state of 5-OT-ergic system.     

Evidence that growth hormone exerts a feedback effect on stomach ghrelin production and secretion

Ghrelin is a recently discovered stomach hormone that stimulates pituitary growth hormone (GH) secretion potently. The purpose of these experiments was to test the hypothesis that a stomach-ghrelin-pituitary-GH axis exists in which either an elevation or reduction in systemic GH levels will exert a negative or positive feedback action, respectively, on stomach ghrelin homeostasis. In rats, GH administration decreased stomach ghrelin mRNA levels and plasma ghrelin levels significantly. In GH-releasing hormone (GHRH) transgenic mice, GHRH overexpression decreased stomach ghrelin peptide levels when compared with control mice. In aged rats (25 months) stomach ghrelin mRNA and peptide levels and plasma ghrelin levels were decreased when compared with young rats (5 months). Because GH secretion is reduced in aged rats, the elevated stomach ghrelin production and secretion may reflect a decreased GH feedback on stomach ghrelin, homeostasis, and secretion. Together, these findings suggest that endogenous pituitary GH exerts a feedback action on stomach ghrelin homeostasis and support the hypothesis that a stomach-ghrelin-pituitary GH axis exists.     

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

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.     

Ciprofibrate stimulates the gastrin-producing cell by acting luminally on antral PPAR-alpha

The lipid-lowering drug ciprofibrate stimulates gastrin-producing cells in the rat stomach without lowering gastric acidity. Although suggested to be a luminal action on antral peroxisome proliferator-activated receptor-alpha (PPAR-alpha), the mechanism is still not fully elucidated. Gastric bypass was surgically prepared in male Sprague-Dawley rats. Gastric-bypassed and sham-operated rats were either given ciprofibrate (50 mg.kg(-1).day(-1) in methocel) or vehicle alone for 7 wk. PPAR-alpha knockout (KO) and wild-type (WT) mice were either given ciprofibrate (500 mg.kg(-1).day(-1) in methocel) or vehicle alone for 2 wk. The concentration of gastrin in blood was analyzed. Antral G cell density and gastrin mRNA abundance were determined by using immunostaining and Northern blot analysis. Ciprofibrate did not raise plasma gastrin or G cell density in gastric-bypassed rats, although the gastrin mRNA level was slightly increased. In contrast, ciprofibrate induced hypergastrinemia, a 50% increase in G cell density, and a threefold increase in gastrin mRNA in sham-operated rats. In PPAR-alpha KO mice, ciprofibrate did not raise G cell density or the gastrin mRNA level. The serum gastrin level was reduced by ciprofibrate. In WT mice, ciprofibrate induced hypergastrinemia, a doubling of G cell density, and a threefold increase in gastrin mRNA. Comparing animals dosed with vehicle only, PPAR-alpha KO mice had higher serum gastrin concentration than WT mice. We conclude that the main effects of ciprofibrate on G cells are mediated from the antrum lumen, and the mechanism is dependent on PPAR-alpha. The results indicate that PPAR-alpha may have a role in the physiological regulation of gastrin release.     

Effects of zinc-aspartate and zinc-glycinate in healthy rats and on reserpine-induced gastric lesions

Experimental studies performed on 227 rats showed that Zn-aspartate and Zn-glycinate administered ip lowered the incidence, number, and severity of the reserpine-induced gastric lesions ensuring significant protection indices. Histochemical methods revealed increased amount of mucosal glycoproteins. The activity of dehydrogenases involved in energy metabolism that modulates acid secretion in the parietal cells was depressed. RNA content in the chief cells as premises of pepsinogen synthesis, was decreased. ATPase reaction in the periglandular capillaries was uniform and stronger, showing an improvement of gastric mucosal microcirculation. Since these histochemical changes were also noted in healthy rats receiving Zn salts, it might be suggested that they are not the mere expression of an anti-ulcer protective effect of zinc, but rather reflect its mechanism of action, relating to the complex metabolic events induced by the trace element. Our results are in agreement with those previously reported concerning the noxious influence of Zn depletion, the accelerated healing of peptic ulcer patients after Zn treatment, and the protective effect of Zn against ulcerogenesis in several experimental models involving different pathomechanisms.     

Capsaicin-sensitive afferent sensory nerves in modulating gastric mucosal defense against noxious agents.

In the rat stomach, evidence has been provided that capsaicin-sensitive sensory nerves (CSSN) are involved in a local defense mechanism against gastric ulcer. In the present study capsaicin or resiniferatoxin (RTX), a more potent capsaicin analogue, was used to elucidate the role of these sensory nerves in gastric mucosal protection, mucosal permeability, gastric acid secretion and gastrointestinal blood flow in the rat. In the rat stomach and jejunum, intravenous RTX or topical capsaicin or RTX effected a pronounced and long-lasting enhancement of the microcirculation at these sites, measured by laser Doppler flowmetry technique. Introduction of capsaicin into the rat stomach in very low concentrations of ng-microg x mL(-1) range protected the gastric mucosa against damage produced by topical acidified aspirin, indomethacin, ethanol or 0.6 N HCl. Resiniferatoxin exhibited acute gastroprotective effect similar to that of capsaicin and exerted marked protective action on the exogenous HCl, or the secretagogue-induced enhancement of the indomethacin injury. The ulcer preventive effect of both agents was not prevented by atropine or cimetidine treatment. Capsaicin given into the stomach in higher desensitizing concentrations of 6.5 mM markedly enhanced the susceptibility of the gastric mucosa and invariably aggravated gastric mucosal damage evoked by later noxious challenge. Such high desensitizing concentrations of capsaicin, however, did not reduce the cytoprotective effect of prostacyclin (PGI2) or beta-carotene. Capsaicin or RTX had an additive protective effect to that of atropine or cimetidine. In rats pretreated with cysteamine to deplete tissue somatostatin, capsaicin protected against the indomethacin-induced mucosal injury. Gastric acid secretion of the pylorus-ligated rats was inhibited with capsaicin or RTX given in low non-desensitizing concentrations, with the inhibition being most marked in the first hour following pylorus-ligation. Low intragastric concentrations of RTX reduced gastric hydrogen ion back-diffusion evoked by topical acidified salicylates. It is concluded that the gastropotective effect of capsaicin-type agents involves primarily an enhancement of the microcirculation effected through local release of mediator peptides from the sensory nerve terminals. A reduction in gastric acidity may contribute to some degree in the gastric protective action of capsaicin-type agents. The vasodilator and gastroprotective effects of capsaicin-type agents do not depend on vagal efferents or sympathetic neurons, involve prostanoids, histaminergic or cholinergic pathways.     

Sensitivity of hypothalamic neurons to beta-endomorphin, met-enkephalin, and thyroliberin

A study was made of susceptibility of hypothalamic neurons to beta-endorphine, thyroliberin and met-enkephalin applied microiontophoretically. The opioids were shown to exert a primarily unidirectional effect on the same neurons irrespective of the fact that the inhibitory action of beta-endorphine was more pronounced. The nalorphine-competitive antagonist of the opiates removed the met-enkephalin-induced inhibition. Unlike opioids, thyroliberin largely activated the test neurons. The possibility of neuropeptide participation in the control of gonadotropic function of the pituitary is discussed.     

Gastric Cytoprotection and honey intake in Albino Rats

Beneficial effect of honey has been widely reported particularly on wound healings, gastrointestinal disorders and as antibacterial agent. However, there is paucity of report on its cytoprotective effect on the gastric mucosa despite its common usage worldwide including Nigeria. This study was therefore carried out to evaluate the effect of this widely consumed substance on gastric mucosa using animal model and also to explore possible mechanism of its action on the gastric mucosa .Twenty male adult albino rats of Wistar strain, weighing between 210-220g were used in the experiment. They were randomly assigned into two groups, the control group and the honey-fed (test) group, each containing ten rats. The Control group was fed on normal rat feed and water while the test group was fed on normal rat feed with honey added to its drinking water (1ml of honey for every initial 10ml of water for each rat daily) for twenty two weeks. After twenty two weeks the rats were weighed after being starved overnight. They were anaesthetized with urethane (0.6ml/100g body weight). Gastric ulceration was induced using 1.5ml acid-alcohol prepared from equivolume of 0.1NHCl and 70% methanol introduced into the stomach via a portex cannula tied and left in place following an incision made on the antral-pyloric junction of the stomach. The acid-alcohol was allowed to stay for 1hr. After 1hr, laparatomy was performed and the stomach isolated, cut open along the greater curvature, rinsed with normal saline and fastened in place with pins on a dissecting board for ulcer examination and scores. The result obtained showed mean ulcer scores of 14.5+0.70 for the control group and 1.6+0.11 for the test group. The result showed that honey significantly reduced ulcer scores as well as caused scanty haemorrhage in the test group compared with increased ulcer scores and multiple haemorrhage in the control group. It is therefore concluded that honey intake offered cytoprotection on the gastric mucosa of albino rats. Keywords: Honey, Gastric mucosa, Cytoprotection.     

Effects of streptozotocin-induced long-term diabetes on parietal cell function and morphology in rats

Gastric pathology is a common complication in diabetes mellitus. The aim of the study was to evaluate the functions and morphological changes of the parietal cells of the rat stomach after streptozotocin-induced diabetes. Diabetes mellitus was induced in Wistar rats by a single intraperitoneal injection of streptozotocin (60 mg/kg body weight). The rats were weighed weekly and sacrificed after 6 months. The glandular portion of the stomach was removed and processed for H⁺-K⁺-ATPase immunohistochemistry and light and electron microscopy studies. Acid secretion was measured in vivo. After 6 months of diabetes, the mean weight of the rats was significantly lower (P < 0.001) compared to control. The mean weight of the stomach to body weight percentage increased significantly (P < 0.001) compared to control. The blood glucose level in diabetic rats was significantly higher (P < 0.001) than in normal control. Diabetic rats showed significant (P < 0.001) decrease in basal and stimulated acid secretion when compared to control. Electron micrographs of the parietal cells of glandular stomach of diabetic rats revealed significant (P < 0.0002) reduction in the number of mitochondria and a small though not significant increase in the number of canaliculi in the parietal cells compared with normal. Immunohistochemistry showed reduced H⁺-K⁺-ATPase (P < 0.00001) compared to control. Long-term diabetes induces morphological as well as functional changes in gastric parietal cells. The decrease in the number of mitochondria accompanied by reduced in H⁺-K⁺-ATPase in parietal cells may explain the reduced acid secretion observed in diabetics.     

A biochemical analysis of the possible mechanisms of the ulcerostatic action of atranes

Stimulatory effect of metalloatrans on the development of stomach wall connective tissue components was examined in rats with experimental acetate ulcer. Metalloatrans were shown to inhibit peroxide oxidation processes of lipids in blood and stomach tissue.     

The interaction between walker tumour cells and mucosa cells in the lamina propria of gastric mucosa in rats

One series of 12 rats was exposed to X-irradiation (1500 R) of the stomach 19 days before implantation of Walker tumour cells in the gastric mucosa, and the frequency of tumour take and the extent of tumour growth after 10 days were compared with a second series with the same tumour implantation, but without X-ray exposure. In a third series simple gastric ulcers without tumour were produced by clamping the gastric wall with a heated (80 degrees) surgical needle holder, and the animals were killed 5-7 day later. All the rats were given injections of vinblastine sulfate 3 hours and of 3H-TDR 1 hour before sacrifice. In viewfields with diameter 180 mu the vinblastine-arrested mitoses and labelled cells on the tumour side of the tumour/mucosa border were calculated as percentages of all tumour cells. In the mucosa the total number of proliferating cells was counted at various distances from the border of the tumour or ulcer. No clear differences in the frequency of tumour take and the extent of tumour growth were found between the X-irradiated and the normal rat stomachs, and it is concluded that the X-ray exposure 3 weeks prior to tumour implantation did not reduce the normal mucosal resistance to tumour growth. The percentage of arrested mitoses and labelled cells in the tumour decreased one view field away from the mucosal border, and the number of proliferating cells in the mucosa bordering on the tumours showed a gradual fall with increasing distance up to 0.8-1.0 mm from the tumour border; within these distances, however, the numbers were much higher than at corresponding distances from edges of the ulcers. The Walker tumour thus seems to stimulate cell proliferation in mucosa to a much greater extent than a simple ulcer does. The causes of this phenomenon and the possible roles of "chalones" or "anti-chalones" are discussed.