Healing Of Gastric Ulcers In Rats Research Articles

Immunoreactivity of infiltrating macrophages during gastric ulcer healing in rats

Immunoreactivity of infiltrating macrophages during gastric ulcer healing in rats

Effect and mechanism of Jingqi Yukui Capsules on gastric ulcer mucosa healing quality: based on network pharmacology and animal experiment

This study aims to identify the active components and the mechanism of Jingqi Yukui Capsules(JQYK) in the treatment of gastric ulcer based on network pharmacology, and verify some key targets and signaling pathways through animal experiment. To be specific, first, the active components and targets of JQYK were retrieved from a Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine(BATMAN-TCM) and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), and the targets of gastric ulcer from GeneCards and Online Mendelian Inheritance in Man(OMIM) with the search term "gastric ulcer". The common targets of the two were the potential targets of the prescription for the treatment of the di-sease. Then, protein-protein interaction(PPI) network of key targets were constructed based on STRING and Cytoscape 3.7.2, followed by Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment by matescape database and pathway visualization by Omicshare. For the animal experiment, the improved method of Okabe was used to induce gastric ulcer in rats, and the model rats were classified into the model group, JQYK high-dose(JQYK-H), medium-dose(JQYK-M), and low-dose(JQYK-L) groups, Anweiyang Capsules(WYA) group, and Rabeprazole Sodium Enteric Capsules(RBPZ) group. Normal rats were included in the blank group. Rats in the blank group and model group were given distilled water and those in the administration groups received corresponding drugs. Then gastric ulcer healing in rats was observed. The changes of the gastric histomorphology in rats were evaluated based on hematoxylin-eosin(HE) staining, and the content of inducible nitric oxide synthase(iNOS) in rat gastric tissue was detected with Coomassie brilliant blue method. The mRNA and protein levels of some proteins in rat gastric tissue were determined by real-time quantitative polymerase chain reaction(RT-qPCR) and Western blot(WB) to further validate some key targets and signaling pathways. A total of 206 active components and 535 targets of JQYK, 1 305 targets of gastric ulcer, and 166 common targets of the disease and the drug were yielded. According to PPI analysis and KEGG pathway enrichment analysis, multiple key targets, such as interleukin-6(IL-6), tumor necrosis factor(TNF), mitogen-activated protein kinase 1(MAPK1), MAPK3, and MAPK14, as well as nuclear factor kappa-B(NF-κB) signaling pathway, IL-17 signaling pathway, and leukocyte transendothelial migration in the top 20 key signaling pathways were closely related to inflammation. The key protein p38 MAPK and NF-κB signaling pathway were selected for further verification by animal experiment. The gastric ulcer in the JQYK-H group recovered nearly to the level in the blank group, with significant decrease in the content of iNOS in rat gastric tissue and significant reduction in the mRNA and phosphorylation levels of p38 MAPK and the mRNA and protein levels of NF-κB p65 in rat gastric tissue. The results indicated that JQYK can inhibit the phosphorylation of the key protein p38 MAPK and the expression of NF-κB p65 in the NF-κB signaling pathway, thereby exerting the anti-inflammatory effect and effectively improving the quality of gastric ulcer healing in rats. Thus, the animal experiment result verifies some predictions of network pharmacology.

Ethanolic Stem Bark Extract of Boswellia dalzielli H Promotes the Healing of Acetic Acid Induced Chronic Gastric Ulcer by Down-Regulation of Tumor Necrosis Factor (TNF) -Αlpha in Wistar Albino Rats

The present study determines the effects of the ethanolic stem bark extract of Boswellia dalzielii H on gastric homogenate and serum levels of TNF-α and vascular endothelial growth factor (VEGF), during the healing of chronic gastric ulcer induced by acetic acid in Wistar albino rats. Round and deep chronic gastric ulcers were induced by a high concentration of acetic acid in Wistar albino rats. 75 rats with gastric ulcers were randomly assigned to five treatment groups (2-5). Rats in group 1 had no gastric ulcer and were administered with vehicle 5ml/kg. Rats in group 2, negative control had gastric ulcers and were treated with vehicle 5ml/kg. Rats in group 3 were treated with ranitidine (50mg/kg) while rats in groups 4, 5, and 6 were treated daily with 100, 200, and 400mg/kg of ethanolic stem bark extract of Boswellia dalzielli H respectively. Treatment in all the groups was by intragastric administration. Five rats from groups (2-6) were euthanized on days 3, 7, and 9 along with the control group (1). Blood was collected, serum prepared, and assayed for TNFα and VEGF using ELISA. The stomach of each animal was evaluated for gastric ulcer, assessed for histopathologic changes, and preparation of gastric tissue homogenates. Intragastric administration of graded doses of ethanolic stem bark extract of Boswellia dalzielli H and ranitidine (50mg/kg) respectively, down-regulated serum and gastric tissue levels of TNF–α significantly (p<0.05), up-regulated VEGF significantly (p<0.05), and increased gastric ulcer healing rate in a significant manner (p<0.05). The increase was time and Dose and time dependent manner when compared to control. Attenuation of TNFα and up-regulation of VEGF by graded intragastric administration of the ethanolic stem bark extract of Boswellia dalzielli promotes the healing of chronic gastric ulcer induced by acetic acid in Wister albino rats.

Effectiveness of the polyphenols-rich Sedum dendroideum infusion on gastric ulcer healing in rats: Roles of protective endogenous factors and antioxidant and anti-inflammatory mechanisms

Ethnopharmacological relevancePeptic ulcer is an inflammatory disease that therapeutic options are mainly focused in antisecretory drugs. Sedum dendroideum Moc & Sessé ex DC (Crassulaceae) is employed in folk medicine for the treatment of gastric ulcers. Recently, our group demonstrated that Sedum dendroideum infusion (SDI) is rich in polyphenols (flavonol glycosides, myricetin, quercetin and kaempferol) and promoted gastroprotection against acute ulcer models, without changes gastric acid secretion. Aim of the studyHere, we follow the investigation of the healing effects of SDI (ED50 = 191 mg/kg) in the chronic gastric ulcer model induced by 80% acetic acid in rats, elucidating underlying mechanisms. Material and methodsRats were orally treated with vehicle (water, 1 mL/kg), SDI (191 mg/kg), omeprazole (40 mg/kg) or sucralfate (100 mg/kg) twice daily for 5 days after ulcer induction. Following treatments, toxicological effects, macroscopic ulcer appearance, microscopic histological (HE, mucin PAS-staining) and immunohistochemical (PCNA and HSP70) analysis, inflammatory (MPO and NAG activity, cytokine levels measurements) and antioxidant (SOD and CAT) parameters were investigated in gastric ulcer tissues. ResultsOral treatment with SDI accelerated gastric ulcer healing, maintained mucin content and promoted epithelial cell proliferation. SDI also reduced neutrophil and mononuclear leukocyte infiltration, TNF-α and IL-1β levels and the oxidative stress, restoring SOD and CAT activities in the ulcer tissue. ConclusionsThe gastric healing effect of SDI was mediated through endogenous protective events as well as due to the anti-inflammatory and antioxidant actions. Our observations support and reinforce the traditional utilize of Sedum dendroideum as a natural nontoxic therapeutic alternative for the treatment of gastric ulcers.

Chrysophyllum Albidum Accelerates Delayed Gastric Ulcer Healing in Rats Through Oxidative Stress Reversal and Proton Pump Inhibition

Background: Chrysophyllum albidum has been documented to exert its gastric ulcer (GU) healing activities by modulating blood inflammatory mediators, however, other probable in-vivo underlying mechanisms are still vague which this study sought to investigate.Materials and Methods: Male Wistar rats (120-130g) divided into 9 groups (n=15 for groups I-VII; n=5 for groups VIII & IX) viz: Groups I- positive control (DUnA); II and III–250 and 500mg/kg methanolic extract of C. albidum (MeCaB) bark respectively; IV, V and VI-100mg/kg fractions A, B and C respectively; VII–30mg/kg omeprazole; VIII-ulcerated untreated (baseline), IX-negative control. Chronic GU was induced experimentally and delayed using indomethacin with 14 days simultaneous drug treatment. Gastric ulcer score, mucin content, antioxidant and proton pump activities were evaluated by days 3, 7 and 14 of treatment. Data were expressed as Mean+SEM and P<0.05 was significant.Results: C. albidum and fractions treated groups significantly decreased gastric ulcer scores and lipid peroxidation compared with DUnA. Negative control, C. albidum and fraction treated groups significantly increased superoxide dismutase, catalase, glutathione levels and mucin content compared with DUnA group by days 3 and 7. C. albidum, Negative and baseline control groups significantly decreased H+K+ATPase activities compared with DUnA by day14.Conclusion: C. albidum and its fractions facilitated the healing of gastric ulcer, probably by enhanced antioxidant levels, mucin content and decreased gastric H+K+ATPase activity.
 Keywords: C. albidum and chromatographic fractions, gastric ulcer healing, mucin , antioxidant, H+/K+ATPase pump.

The essential oil from Baccharis trimera (Less.) DC improves gastric ulcer healing in rats through modulation of VEGF and MMP-2 activity

Ethnopharmacological relevanceBaccharis trimera (Less.) DC known as “carqueja” in Brazil has been acknowledged as a medicinal plant in folk medicine for the treatment of stomach aches and gastrointestinal disorders. Aim of the studyThe present study aimed to evaluate the gastroprotective and healing effects of essential oil from B. trimera (EOBT) against gastric ulcer lesions caused by absolute ethanol and acetic acid, respectively, and to identify the mechanism of action of this essential oil in male Wistar rats. Materials and methodsThe plant material used to obtain EOBT was collected in the southern region of Brazil and was analyzed by chromatography-mass spectrometry (GCMS) demonstrate its characteristic chemical composition, with carquejyl acetate as its main component. Different doses of EOBT (50, 100, and 200 mg/kg) were administered orally in male Wistar rats as an acute treatment against absolute ethanol-induced gastric lesions. The gastric healing effect of EOBT (100 mg/kg) was evaluated once a day after 7, 10, and 14 days of treatment. After treatment, the stomachs of rats from all groups were collected to measure the lesion area (mm2), the activity of myeloperoxidase (MPO), and the relative expression of caspases −3, −8, −9, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). The zymography method was used to elucidate the activity of matrix metalloproteinase-2 (MMP-2) and −9 (MMP-9) in the healing action of EOBT. We also analyzed toxicological parameters (body weight evolution and biochemical parameters) that could result after treatment with this essential oil for 14 days. ResultsPretreatment with EOBT (100 and 200 mg/kg) significantly decreased the severity of gastric damage induced by absolute ethanol and decreased MPO activity in gastric tissue. After 10 and 14 days of treatment with EOBT (100 mg/kg) once a day, the lesion area was significantly reduced by 61% and 65.5%, respectively, compared to the negative control group. The gastric healing effect of EOBT was followed by a decrease in the expression of COX-1 compared to that in the negative control group. Notably, treatment with EOBT for 14 days increased the expression of VEGF compared to that using an anti-ulcer drug (lansoprazole). Additionally, analyses of MMP-2 and MMP-9 activities in the gastric mucosa confirmed the accelerated gastric healing effect of EOBT, with a significant decrease in the activity of pro-MMP-2. No sign of toxicity was observed after treatment with EOBT for 14 consecutive days. Conclusion: These findings indicated that EOBT was effective in preventing and accelerating ulcer healing by decreasing MPO activity, increasing VEGF expression, and decreasing MMP-2 activity. These actions collectively contribute to the rapid recovery of gastric mucosa following treatment with EOBT, without any observed toxicity.

Healing Effect of Rebamipide in Addition to Omeprazole for Gastric Ulcer: Preliminary Results of a Randomized, Double-blind, Placebo-controlled Trial

Background: Rebamipide is a mucoprotective agent which has anti-oxidative and anti-inflammatory effects, as well as the ability to increase mucosal blood flow. From theoretical basis, addition of rebamipide to proton pump inhibitors (PPI) may facilitate the healing of gastric ulcer (GU). Objective: To compare the GU healing rates between treatment with a combination of rebamipide plus omeprazole and omeprazole monotherapy Materials and Methods: This double-blind, randomized, placebo-controlled trial was conducted at Rajavithi Hospital, Bangkok between 2018-2019. Patients with GU size 0.5-3 cm were randomly assigned into either combination group (omeprazole 20 mg OD + rebamipide 100 mg TID) or PPI monotherapy group (omeprazole 20 mg OD + placebo). Primary endpoint was healed GU after 4 weeks of treatment determined by follow-up esophagogastroduodenoscopy.   Results: A total of 70 patients were randomized and 64 completed the study. The proportion of patients with non-steroidal anti-inflammatory drugs (NSAIDs) use and Helicobacter pylori positive were 42.9% and 68.6% in the combination group, 62.9% and 60% in the PPI group, without statistically significant difference. Overall, healed GU occurred in 77.1% in the combination group, and 60% in the PPI group, as intention-to-treat analysis (p=0.198). Mean change of size of GU was -0.8 cm (-1, -0.60) in the combination group, and -0.68 cm (-0.81, -0.55) in the PPI group (p=0.3). In subgroups analysis, patients with the presence of H. pylori , atrophic gastritis and/or intestinal metaplasia, NSAIDs use and current smoking have higher rates of healed GU by the combination therapy compared with PPI alone (p>0.05). There were no differences in compliance and treatment side effects between the two groups. Conclusion: Treatment with rebamipide plus PPI has a trend toward improved GU healing, compared with PPI monotherapy, especially in subgroup of patients with features of difficult to heal GU (presence of H. pylori , atrophic gastritis, intestinal metaplasia, NSAIDs and smoking). Keywords: Gastric ulcer, Mucoprotective drug, Omeprazole, Peptic ulcer disease, Proton pump inhibitor, Rebamipide

Immunohistochemical Studies of Age-Related Changes in Cell Proliferation and Angiogenesis during the Healing of Acetic Acid-Induced Gastric Ulcers in Rats.

Cell proliferation and angiogenesis are of utmost importance for healing to take place. The KI67 and EGFR proteins are markers of cell proliferation, while CD31 and factor VIII are markers of angiogenesis. To elucidate the mechanism responsible for delayed healing of the gastric injury in old age, we analyzed the expression of these markers in rats of different months during the healing of an acetic acid-induced gastric ulcer. Male Wistar rats (aged 3, 6, 12, and 18 months) divided into four groups, according to their ages, formed the experimental animals. Stomach tissue samples were collected on days 3, 7, 14, and 21 after induction for assessment of ulcer healing. The area of gastric mucosa healed was inversely proportional to age. The expression of markers of proliferation (KI67 and EGFR) and angiogenesis (factor VIII and CD31) decreased significantly (p < 0.05) in older rats when compared with younger ones (3 months > six months > 12 months > 18 months) on days 7, 14, and 21 after induction of gastric ulcer. This study revealed that the slower gastric ulcer healing rate in older rats might be due to reduced epithelial cell proliferation and angiogenic activities.

Sex-specific effects of Eugenia punicifolia extract on gastric ulcer healing in rats.

AIMTo evaluate the sex-specific effects of a hydroalcoholic extract from Eugenia punicifolia (HEEP) leaves on gastric ulcer healing.METHODSIn this rat study involving males, intact (cycling) females, and ovariectomized females, gastric ulcers were induced using acetic acid. A vehicle, lansoprazole, or HEEP was administered for 14 d after ulcer induction. Body weight was monitored throughout the treatment period. At the end of treatment, the rats were euthanized and the following in vivo and in vitro investigations were performed: macroscopic examination of the lesion area and organ weights, biochemical analysis, zymography, and evaluation of protein expression levels. Additionally, the concentration-dependent effect of HEEP was evaluated in terms of subacute toxicity and cytotoxicity.RESULTSCompared to the vehicle, HEEP demonstrated a great healing capacity by substantially reducing the ulcerative lesion area in males (52.44%), intact females (85.22%), and ovariectomized females (65.47%), confirming that HEEP accelerates the healing of acetic acid-induced gastric lesions and suggesting that this effect is modulated by female sex hormones. The antiulcer effect of HEEP was mediated by prostaglandin E2 only in male rats. Overall, the beneficial effect of HEEP was the highest in intact females. Notably, HEEP promoted the expression of vascular endothelial growth factor (intact vs ovariectomized females) and decreased the expression of Caspase-8 and Bcl-2 (intact female vs male or ovariectomized female). Additionally, HEEP enhanced fibroblast proliferation and migration into a wounded area in vitro, confirming its healing effect. Finally, no sign of subacute toxicity or cytotoxicity of HEEP was observed.CONCLUSIONIn gastric ulcers, HEEP-induced healing (modulated by female sex hormones; in males, mediated by prostaglandin) involves extracellular matrix remodeling, with gastric mucosa cell proliferation and migration.

Effects of artemisinin, with or without lumefantrine and amodiaquine on gastric ulcer healing in rat.

Abstract Background Antimalarial drugs have been shown to predispose the stomach to ulceration in rats. However, their role in the modulation of gastric ulcer healing is not known. The aim of the present study is to investigate the effect of artemisinin-based combination therapies on ulcer healing. Methods Gastric kissing ulcers were induced in 40 male albino rats (150–180 g) using 0.2 mL 50% acetic acid. One day after the ulcer induction, experimental rats were divided into four groups and treated once daily orally for 3 days as follows: (1) normal saline, (2) artemether-lumefantrine (2/12 mg/kg), (3) artesunate-amodiaquine (4/10 mg/kg), and (4) artesunate (2 mg/kg) only. A fifth group of 10 rats served as overall control with no ulcer induced and no treatment given. Ulcer healing was determined on days 4 and 7 post induction using ulcer score and planimetry. Results Artesunate decreased ulcer severity by 12.5% and 52.0% on days 4 and 7, respectively. Significant increases in severity were observed in rats treated with artemether-lumefantrine (25.0% and 40.0%) and artesunate-amodiaquine (50.0% and 95.0%). Lipid peroxidation was decreased by artesunate by day 7 (27%; p&lt;0.05) but increased in artemether-lumefantrine and artesunate-amodiaquine administered rats (63.6% and 55%; p&lt;0.05). The activity of superoxide dismutase was reduced by artesunate-amodiaquine on day 7 (22%; p&lt;0.05) but no effect in the artemether-lumefantrine treatment. Neutrophil infiltration, total leukocyte count, neutrophil-lymphocyte ratio, and C-reactive protein values were significantly increased in the artemether-lumefantrine and artesunate-amodiaquine treated groups when compared with the untreated ulcer control group (p&lt;0.05). These variables were all reduced by artesunate (p&lt;0.05). Conclusions This study revealed that although artesunate may be beneficial in gastric ulcer healing, its combination with either lumefantrine or amodiaquine may delay healing of gastric mucosal injury.

Efficacy and safety of Helicobacter pylori eradication therapy immediately after endoscopic submucosal dissection.

In the treatment of patients after endoscopic submucosal dissection (ESD), there is no consensus on the optimum time to start Helicobacter pylori eradication therapy or on whether eradication therapy improves ulcer healing rate after ESD. The aim of this study was to examine the effect of immediate eradication of H.pylori on ulcer healing after ESD in patients with early gastric neoplasms. A total of 330 patients who underwent ESD for early gastric neoplasms were enrolled. Patients were assigned to either H.pylori eradication group (Group A: H.pylori eradication+proton pump inhibitor 7weeks) or non-eradication group (Group B: proton pump inhibitor 8weeks). The primary end point was gastric ulcer healing rate (Group A vs Group B) determined on week 8 after ESD. Patients in Group A failed to meet non-inferiority criteria for ulcer scarring rate after ESD compared with that in Group B (83.0% vs 86.5%, P for non-inferiority=0.0599, 95% confidence interval: -11.7% to 4.7%). There were, however, neither large differences between the two groups in the ulcer scarring rate nor the safety profile. This study failed to demonstrate the non-inferiority of immediate H.pylori eradication therapy after ESD to the non-eradication therapy in the healing rate of ESD-caused ulcers. However, because the failure is likely to attribute to small number of patients enrolled, immediate eradication therapy may be a treatment option for patients after ESD without adverse effects on eradication therapy in comparison with the standard therapy.

Vonoprazan: A Novel and Potent Alternative in theTreatment of Acid-Related Diseases.

Although proton pump inhibitors (PPIs) have been used widely, acid-related diseases are still associated with a huge burden on the health care system. Recently, the efficacy and safety of a new acid suppressant named vonoprazan in the treatment of acid-related diseases have been evaluated by a series of studies. As a novel potassium-competitive acid blocker, vonoprazan may provide reversible acid suppression by preventing K+ from binding to gastric H+/K+-ATPase. It has been clinically used for the short-term treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease and Helicobacter pylori (H. pylori) infection in Japan. The healing rate of GERD and gastric ulcers by vonoprazan is more than 95 and 90%, respectively; also, it is effective in curing PPI-resistant GERD. It increases H. pylori eradication rate to more than 88% as part of both first-line and second-line therapy. It is also effective in the eradication of clarithromycin-resistant H. pylori strains. All of these short-term studies show vonoprazan is safe and well-tolerated. As a safe and effective acid inhibitor, vonoprazan might be a novel alternative in the treatment of acid-related diseases.

Antiplatelet drug ticagrelor delays gastric ulcer healing in rats.

Adenosine diphosphate P2Y12 receptor antagonist clopidogrel is not sufficiently safe for the gastric mucosa in patients with high risk of peptic ulcer, since it may impair healing of gastric erosions. However, the safety of the novel P2Y12 receptor antagonist ticagrelor in the gastric mucosa has not been elucidated to date. The present study aimed to examine whether ticagrelor delays gastric ulcer healing and to elucidate the involved mechanisms. Gastric kissing ulcers were produced in rats by luminal application of acetic acid solution, and ticagrelor was administered at dose of 10 or 20 mg/kg/day orally for 7 days. On day 8 after ulcer induction, the ulcer size, mucosal epithelial cell proliferation of the ulcer margin, expression levels of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), and signal transduction pathways for cell proliferation and angiogenesis were measured and compared between the ticagrelor-treated and untreated model groups. The results revealed that the ulcer size was significantly greater in the ticagrelor-treated group compared with the model group, while the mucosal epithelial cell proliferation of the ulcer margin was significantly decreased in the ticagrelor-treated group. In addition, ticagrelor significantly decreased the ulcer-stimulated expression levels of EGF, VEGF, phosphorylated extracellular signal-regulated kinase (ERK), phosphorylated P38 mitogen-activated protein kinase and nuclear factor-κB P65 at the ulcer margin (P<0.05). These findings suggested that ticagrelor delayed gastric ulcer healing. Furthermore, the possible mechanisms underlying the effect of ticagrelor were associated with its functions of attenuating the expression levels of VEGF and EGF, as well as suppressing the phosphorylation activation of ERK1/2, P38 and nuclear factor-κB P65. Finally, the gastric epithelial cell proliferation and angiogenesis were also inhibited.

Analyzing the influence of gastric intestinal metaplasia on gastric ulcer healing in Helicobacter pylori\u2013infected patients without atrophic gastritis

BackgroundGastric epithelial hyper-proliferation was reported in patients with Helicobacter pylori (H. pylori)–infected gastric mucosa with intestinal metaplasia (IM) changes. In patients with gastric ulcer (GU) and IM, the GU may have a different healing rate in comparison to patients without IM. This study aimed to compare the difference in GU healing between H. pylori–infected patients with IM and those without IM.MethodsWe retrospectively analyzed patients at the Keelung Chung Gung Memorial Hospital during the period from March 2005 to January 2011. The inclusion criteria were: 1) endoscopic findings of GU and biopsy histological examination plus rapid urease test indicating H. pylori infection; 2) gastric IM adjacent to a GU but with no atrophic gastritis changes; 3) patients receiving H. pylori eradication triple therapy and 8 weeks of maintenance therapy with a proton pump inhibitor; and 4) patients receiving follow-up endoscopy within the 3rd and the 4th months after treatment.ResultsIn total, 327 patients with GU and H. pylori infection (136 with IM and 191 without IM) were included. Patients with IM had a higher GU healing rate than those without IM (91.9% vs. 84.3%, P = 0.040). Multivariate logistical regression analysis revealed that failure of H. pylori eradication (Odds = 4.013, 95% CI: 1.840–8.951, P < 0.001) and gastric IM (Odds = 0.369, 95% CI: 0.168–0.812, P = 0.013) were the predictors of non-healing GU following treatment.ConclusionsPatient with gastric IM change may have a higher GU healing rate than those without gastric IM. However, successful H. pylori eradication is a more important factor for GU healing than gastric IM.

Gastroprotective potential of melatonin versus melatonin loaded niosomes on gastric ulcer healing in rats

The present study was conducted to investigate the therapeutic effects of melatonin and melatonin-loaded niosomes on ethanol-induced gastric lesions. Morphological and biochemical changes associated with each drug were investigated. Seventy apparently healthy female albino rats, weighting about 200–250 g were randomly assigned to 4 experimental groups. The first group (induction group) included 10 rats that were given 1 ml 70 % ethanol and sacrificed after 1 and 1/2 hour. The second group (melatonin-treated group) included 25 rats that were administrated with 2 mg/rat melatonin by gastric tube daily after induction of ulcer by ethanol. Five rats were sacrificed after 3, 7, 14, 21, and 28 days post-treatment. The third group (melatonin-loaded niosomes treated group) consisted of 25 rats that were given melatonin-loaded niosomes in the same dose and route as the third group. Five rats were sacrificed after 3, 7, 14, 21, and 28 days post-treatment. The fourth group (control group) consisted of 10 rats that administrated only the vehicle in a similar dose and route as other groups (5 rats were given 1 ml of saline and the other 5 rats were given 1 ml of niosomes polymer daily via gastric tube). The rats were kept throughout the time of the study and were sacrificed by cervical dislocation at the end of the experiment. Gross lesions were carried out, and ulcer index was calculated for each subgroup. Tissue samples were fixed in 10 % neutral buffered formalin and stained with Hx&E stain for conventional histological examination. Biochemical analysis of tissue homogenate for determination of lipid peroxidation and total antioxidants was performed. Melatonin-loaded niosomes showed early impressive gastroprotection as early as 7 days post-treatment while unloaded melatonin therapy exerted their effects after 14 days respectively. In addition, melatonin-loaded niosomes improved the micro-vascular damages after 14 days compared to the other melatonin-treated group which showed improved gastric alterations after 21 days. Biochemically, the cases of melatonin-loaded niosomes achieved the lowest mean values of lipid peroxidation and highest mean values of total antioxidants compared to other values recorded in case of unloaded melatonin therapy, and these results are in accordance with that of the histopathological findings.

A study on healing of peptic ulcer disease after eradication of helicobacter pylori infection

There is intimate connection between peptic ulcer &amp; Helicobacter pylori infection. But some uncertainties still surround the relationship between status of H. pylori infection and extent &amp; time required for ulcer healing. This prospective observational study was carried out in the department of Gastroenterology, BSMMU, Dhaka from January 2007 to January 2008 to determine whether the successful eradication of H. pylori leads to adequate ulcer healing. To see the pattern of endoscopic findings in patients still having H. pylori infection after standard triple therapy for H. pylori were also a objective. Eighty nine consecutive patients, aged 15-60 years and of both genders, coming to the gastroenterology outpatient department with the symptoms suggestive of peptic ulcer disease and dyspepsia were included and H. pylori status was defined as positive if both rapid urease test &amp; histopathology were positive. As found in this study, H. pylori was associated with 90% of duodenal ulcers and 80% of gastric ulcers. H. pylori eradication rate was 69%. Healing rate of duodenal ulcer and gastric ulcer after standard triple therapy for 14 days were 80% and 78% respectively. Adequate ulcer healing was achieved in this study despite relatively low eradication rate. Follow-up for additional period is required for recurrence of ulcer in 84 patients whose peptic ulcer disease had resolved but could not attain H. pylori eradication and H. pylori eradicated patients who are still having ulcer at endoscopy DOI: http://dx.doi.org/10.3329/bmj.v43i2.21388 Bangladesh Med J. 2014 May; 43 (2): 84-89

Mechanisms of Esophageal Protection, Gastroprotection and Ulcer Healing by Melatonin. Implications for the Therapeutic use of Melatonin in Gastroesophageal Reflux Disease (GERD) and Peptic Ulcer Disease

Melatonin is a potent reactive oxygen metabolite scavenger and antioxidant that has been shown to influence many physiological functions of the gastrointestinal (GI) tract including secretion, motility, digestion and absorption of nutrients. The role of melatonin in gastroduodenal defense and ulcer healing has been the subject of recent investigations. Melatonin produced in the GI mucosa plays an important role in protection against noxious agents thus contributing to the maintenance of GI integrity and to esophageal protection, gastroprotection and ulcer healing. This review was designed to summarize the involvement of melatonin, conventionally considered as a major hormone of the pineal gland, in the maintenance of gastric mucosal integrity, gastroprotection, ulcer healing and intestinal disorders. Melatonin was originally shown to attenuate gastric mucosal lesions but controversy exists in the literature as to whether melatonin derived from the pineal gland, considered as the major source of this indole, or rather gastrointestinal melatonin plays predominant role in gastroprotection. Intragastric and central administration of exogenous melatonin and L-tryptophan, this indoleamine precursor, affords protection against gastric hemorrhagic damage caused by the exposure of gastric mucosa to variety of non-topical and topical ulcerogens such as stress, ethanol and ischemia-reperfusion. The speed of ulcer healing in experimental animals and humans is accelerated by melatonin. This indoleamine could be also effective against the esophageal lesions provoked by reflux esophagitis in animal models and prevents the incidence of GERD in humans. The melatonin-induced gastroprotection is accompanied by an increase in gastric blood flow, plasma melatonin concentration, enhancement in mucosal generation of PGE2, luminal NO content and plasma gastrin levels. Melatonin scavenges reactive oxygen metabolites, exerts anti-oxidizing and anti-inflammatory actions and inhibits the formation of metalloproteinases- 3 and -9; both implicated in the pathogenesis of gastrointestinal injury and formation of gastric ulcers. Blockade of MT2 receptors by luzindole, significantly attenuated melatonin- and L-tryptophan-induced protection and increased the speed of ulcer healing and these effects were accompanied by an increase in the GBF and luminal content of NO suggesting that melatonin exhibits gastroprotection and hyperemia via activation of MT2 receptors and release of NO. The accumulated evidence indicates that the melatonin-induced gastroprotection and the enhancement in healing rate of gastric ulcers may involve the gastroprotective factors derived from the activation of PG/COX and NO/NOS systems as well as gastrin which also was shown to exhibit protective and trophic effects in the upper GItract. Interestingly, pinealectomy, which suppressed plasma melatonin levels, markedly exacerbated gastric lesions induced by topical and non-topical ulcerogens and these effects are counteracted by a concurrent supplementation with melatonin. Evidence is provided that exogenous melatonin and that converted from its precursor, L-tryptophan, attenuates acute gastric lesions and accelerates ulcer healing via interaction with MT2 receptors due to an enhancement of gastric microcirculation, probably mediated by NO and PG derived from NOS and COX-1 and COX-2 overexpression and activity. The pineal gland plays an important role in the limitation of gastric mucosal injury and the acceleration of ulcer healing via releasing endogenous melatonin, which attenuates oxidative stress and exerts anti-inflammatory action.

SITAGLIPTIN IMPAIRS HEALING OF EXPERIMENTALLY INDUCED GASTRIC ULCERS VIA INHIBITION OF INOS AND COX-2 EXPRESSION

Gastric ulcer healing is a complex process that is regulated by several promoting factors including COX-2 and iNOS. Diabetes mellitus is usually associated with delayed gastric ulcer healing. Hence, the current study was designed to investigate the effect of sitagliptin (dipeptidyl peptidase-4 inhibitor) on gastric ulcer healing and expression of iNOS and COX-2 in rat stomach.The study was conducted on 30 rats divided into three equal groups. Group 1 served as normal control group. Gastric ulcer was induced, by serosal application of acetic acid, in group 2 (ulcer model group) and group 3 (sitagliptin-treated group). Sitagliptin was administrated from day 3 to day 10 in group 3. All rats were sacrificed on day 10 and stomachs were removed for pathological examination and immunohistochemical assessment of COX-2 and iNOS expression. Pathological examination revealed that gastric ulcer healing was significantly impaired in the sitagliptin-treated group as evidenced by the significantly larger ulcerated area and ulcer base maturation impairment.COX-2 and iNOS expression as well as mean MVD were significantly diminished in the sitagliptin-treated group as compared to the ulcer model group. A significant positive correlation was found between COX-2 and iNOS implying their synergistic action. We conclude that sitagliptin significantly impairs gastric ulcer healing in rats possibly through inhibition of iNOS and COX-2 expression. Our results raise the question of whether sitagliptin is advisable in diabetic patients with pre-existing gastric ulcer. Our preliminary experimental findings need to be substantiated by future human studies.

Clopidogrel delays gastric ulcer healing in rats

Clopidogrel is not safe enough for the gastric mucosa in patients with high risk of peptic ulcer. This study aimed to explore if clopidogrel delays gastric ulcer healing and elucidate the involved mechanisms. Gastric ulcer was induced in rats and the ulcer size, mucosal epithelial cell proliferation of the ulcer margin, expression of growth factors [epidermal growth factor (EGF), basic fibroblast growth factor] and their receptors, and signal transduction pathways for cell proliferation were measured and compared between the clopidogrel-treated group and untreated controls. For the in vitro part, rat gastric mucosal epithelial cell line (RGM-1 cells) was used to establish EGF receptor over-expressed cells. Cell proliferation and molecular change under EGF treatment (10ng/ml) with and without clopidogrel (10−6M) were demonstrated. Ulcer size was significantly larger in the clopidogrel-treated group compared to the control and mucosal epithelial cell proliferation of the ulcer margin was significantly decreased in the clopidogrel-treated group (P<0.05). Clopidogrel (2mg and 10mg/kg/day) significantly decreased ulcer-induced gastric epithelial cell proliferation and ulcer-stimulated expressions of EGF receptor and phosphorylated extracellular signal-regulated kinase (PERK) at the ulcer margin (P<0.05). Clopidogrel (10−6M) also inhibited EGF-stimulated EGF receptor, PERK expression, and cell proliferation in RGM-1 cells (P<0.05), and caused much less inhibition of EGF-stimulated cell proliferation in EGF receptor over-expressed RGM-1 cells than in RGM-1 cells (22% vs. 32% reduction). In conclusion, clopidogrel delays gastric ulcer healing in rats via inhibiting gastric epithelial cell proliferation, at least by inhibition of the EGF receptor-ERK signal transduction pathway.

Healing Effects of Rebamipide and Omeprazole in Helicobacter pylori-Positive Gastric Ulcer Patients after Eradication Therapy: A Randomized Double-Blind, Multinational, Multi-Institutional Comparative Study

Background and Aims: A recent placebo-controlled trial showed that rebamipide, which is a mucosal-protective antiulcer agent, promoted gastric ulcer healing without affecting the Helicobacter pylori status. We conducted a randomized, double-blind trial to compare the healing effects of rebamipide and the proton-pump inhibitor omeprazole in H. pylori-positive gastric ulcers after H. pylori eradication therapy. Methods: After completion of 1 week of eradication therapy, 132 patients with H. pylori-positive gastric ulcer were enrolled in 5 Chinese and 4 Korean institutions. Patients were randomly assigned to take either 20 mg of omeprazole (n = 63) or 300 mg of rebamipide (n = 65) daily for 7 weeks. Healing was defined as complete recovery and S1 and S2 stage ulcer according to the Sakita-Miwa classification. Results: Healing rates at 12 weeks were 81.5% (53/65) and 82.5% (52/63) in the rebamipide and omeprazole groups, respectively. There was no significant difference in treatment efficacy, as evidenced by gastric ulcer healing rates (absolute difference –1.0%; 95% confidence interval –10.7 to 8.7; p = 0.88). The H. pylori eradication rate and ulcer healing rate did not differ between the groups, the latter regardless of eradication outcome. Conclusions: Rebamipide is as effective as omeprazole in treating of H. pylori-positive gastric ulcer after eradication therapy.