Indomethacin-induced Gastric Ulcer Research Articles

Gastroprotective Activities of Ethanol Extract of Black Rice Bran (Oryza sativa L.) in Rats.

Black rice is a type of rice in the Oryza sativa L. species. There are numerous reports regarding the pharmacological actions of black rice bran, but scientific evidence on its gastroprotection is limited. This study aimed to evaluate the gastroprotective activities of black rice bran ethanol extract (BRB) from the Thai black rice variety Hom Nil (O. sativa L. indica) as well as its mechanisms of action, acute oral toxicity in rats, and phytochemical screening. Rat models of gastric ulcers induced by acidified ethanol, indomethacin, and restraint water immersion stress were used. After pretreatment with 200, 400, and 800 mg/kg of BRB in test groups, BRB at 800 mg/kg significantly inhibited the formation of gastric ulcers in all gastric ulcer models, and this inhibition seemed to be dose dependent in an indomethacin-induced gastric ulcer model. BRB could not normalize the amount of gastric wall mucus, reduce gastric volume and total acidity, or increase gastric pH. Although BRB could not increase NO levels in gastric tissue, the tissue MDA levels could be normalized with DPPH radical scavenging activity. These results confirm the gastroprotective activities of BRB with a possible mechanism of action via antioxidant activity. The major phytochemical components of BRB comprise carotenoid derivatives with the presence of phenolic compounds. These components may be responsible for the gastroprotective activities of BRB. The 2000 mg/kg dose of oral BRB showed no acute toxicity in rats and confirmed, in part, the safe uses of BRB.

Honokiol mitigates gastric ulcer induced by indomethacin in rats via suppression of inflammatory biomarkers and reactive oxygen species

Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) as indomethacin has been frequently associated with gastric injury. Honokiol (HK) has demonstrated marked hepatoprotective features; however, its effects on indomethacin-induced gastric injury have not been studied. The aim of the study was to evaluate the potential gastroprotective activity of honokiol against indomethacin evoked gastric mucosal damage. Thirty rats were randomly divided into five groups, 6 animals each, and treated for 21 days: the first group (control group), the second group received honokiol only, the third group received indomethacin, the fourth group received honokiol and indomethacin, the fifth group received Omeprazole and indomethacin. The rat's stomachs were examined in terms of the inflammatory and oxidative perturbations. Results demonstrated that HK attenuated the gross gastric damage, scores of ulcer index, area of mucosal lesions, and histopathology outcomes; actions which were similar to the reference antiulcer drug omeprazole, also pretreatment with HK hampered tumor necrosis factor-α (TNF-α) and significantly decreased Malondialdehyde (MDA) level associated with a significant increase in GSH content, total antioxidant capacity (TAC) level and rise in antioxidants enzyme activities namely; catalase (CAT) and glutathione peroxidase (GPx). In conclusion, the available data in this research proposes that the extracts of Honokiol evidenced to be capable of ameliorating indomethacin-induced gastric ulceration and the possible mechanisms are via anti-oxidative and anti-inflammatory.

Syzygium samarangense leaf extract mitigates indomethacin-induced gastropathy via the NF-κB signaling pathway in rats

We previously profiled the chemical composition of wax apple, Syzygium samarangense, leaf extract using HR-LC-MS/MS and reported its antioxidant, hepatoprotective and antitrypanosomal activities. The plant is widely used in traditional medicine to cure several ailments like bronchitis, asthma, diabetes, fever, pathogenic infections, gut spasms, as well as renal diseases. However, neither the gastroprotective effects nor the underlying mechanisms were explored. Here, we investigated the gastroprotective potential of the leaf extract on indomethacin-induced gastric ulcer in rats and explored the involved mechanism(s) of action. Administration of indomethacin significantly increased the ulcer index, mucosal injury, the gastric levels of the inflammatory markers nuclear factor kabba B-p65(NF-κB p65), myeloperoxidase (MPO), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), lipid peroxidation product, malondialdehyde (MDA) and Caspase-3 expression. It reduced the gastric levels of the endogenous antioxidants glutathione as well peroxidase (GPx), reduced glutathione (GSH) and the gastric mucosal protective factors, mucus secretion and goblet cells. Pretreatment with the leaf extract displayed a prominent decrease in the ulcer index, inflammatory cell infiltration, inflammatory markers, MDA, protein expression of Caspase-3 and a significant increase in the gastric levels of the endogenous antioxidants, mucus content and goblet cell proliferation when compared to the indomethacin group. The individual secondary metabolites of the extract exhibited low binding energy when docked into the prostaglandin receptors EP3 and EP4. This study revealed the gastroprotective effect of S. samarangense on indomethacin-induced gastric ulcer in rats. The gastroprotective effects might be attributed to cytoprotective, antioxidant, anti-inflammatory and antiapoptotic activities with a possible potential of activating EP3 and EP4 receptors. In conclusion, S. samarangense has a promising potential in the prevention of NSAIDs-induced ulcers.

Antiulcer Potential of Olea europea L. cv. Arbequina Leaf Extract Supported by Metabolic Profiling and Molecular Docking.

Gastric ulceration is among the most serious humanpublic health problems. Olea europea L. cv. Arbequina is one of the numerous olive varieties which have scarcely been studied. The reported antioxidant and anti-inflammatory potential of the olive plant make it a potential prophylactic natural product against gastric ulcers. Consequently, the main goal of this study is to investigate the gastroprotective effect of Olea europea L. cv. Arbequina leaf extract. LC-HRMS-based metabolic profiling of the alcoholic extract of Olea europea L. cv. Arbequina led to the dereplication of 18 putative compounds (1–18). In vivo indomethacin-induced gastric ulcer in a rat model was established and the Olea europea extract was tested at a dose of 300 mg kg−1 compared to cimetidine (100 mg kg−1). The assessment of gastric mucosal lesions and histopathology of gastric tissue was done. It has been proved that Olea europea significantly decreased the ulcer index and protected the mucosa from lesions. The antioxidant potential of the extract was evaluated using three in vitro assays, H2O2 scavenging, xanthine oxidase inhibitory, and superoxide radical scavenging activities and showed promising activities. Moreover, an in silico based study was performed on the putatively dereplicated compounds, which highlighted that 3-hydroxy tyrosol (4) and oleacein (18) can target the 5-lipoxygenase enzyme (5-LOX) as a protective mechanism against the pathogenesis of ulceration. Upon experimental validation, both compounds 3-hydroxy tyrosol (HT) and oleacein (OC) (4 and 18, respectively) exhibited a significant in vitro 5-LOX inhibitory activity with IC50 values of 8.6 and 5.8 µg/mL, respectively. The present study suggested a possible implication of O. europea leaves as a potential candidate having gastroprotective, antioxidant, and 5-LOX inhibitory activity for the management of gastric ulcers.

Gastro-Protective Effect of Lactoferrin Purified From Cheese Whey and Marjoram Tea Against Indomethacin-Induced Gastric Ulcers

The current study investigated lactoferrin's gastro-protective effect purified from cheese whey and marjoram tea against indomethacin-induced gastric ulcers in rats. Pre-treatment with lactoferrin, marjoram tea, or their combination was conducted for 21 days before introducing gastric ulcers (by a single oral treatment of 30 mg/kg indomethacin). Ulcer index, serum parameters (erythrocyte sedimentation rate, hemoglobin, iron, total iron-binding capacity, lactate dehydrogenase activity, and ferritin), and stomach inflammatory markers (Tumor necrosis factor-alpha and nitric oxide) as well as oxidative markers (malondialdehyde, reduced glutathione, and superoxide dismutase) were assessed. Also, the pathological changes were examined. The pre-treatment with lactoferrin either along with marjoram tea or alone promisingly inhibited the ulcer (77.97 and 60.96 %, respectively). Lactoferrin, marjoram tea, or their combination suppressed the elevation of lactate dehydrogenase activity, ferritin, tumor necrosis factor-alpha, nitric oxide, and malondialdehyde and the reduction of reduced glutathione and superoxide dismutase. The pathological findings revealed that lactoferrin either along with marjoram tea or alone promisingly prevented stomach tissue ulceration. The obtained results suggested the gastro-protective effect of lactoferrin purified from cheese whey and marjoram tea against indomethacin-induced gastric ulcers via their anti-inflammatory and antioxidant activity.

Mechanistic insights into the protective effects of chlorogenic acid against indomethacin-induced gastric ulcer in rats: Modulation of the cross talk between autophagy and apoptosis signaling

BackgroundThis study aimed to investigate the gastroprotective effect of chlorogenic acid (CGA) against Indomethacin (IND)-induced gastric ulcer (GU) in rats and its underlying mechanism, especially through autophagic and apoptotic pathways. MethodsSeventy-five rats were divided into five groups; control, IND (50 mg/kg, p.o.), CGA (100 mg/kg, p.o., 14 days), IND pretreated with CGA (50 mg/kg or 100 mg/kg, p.o., 14 days). The stomach tissues were examined to calculate the ulcer index and analyze markers of autophagy (beclin-1, LC3-II/LC3-I and p62), lysosomal function (cathepsin-D) and apoptosis (Bcl-2, Bax and caspase-3), along with expression of Akt/mTOR pathway using western blot or ELISA techniques. In addition, viability of gastric mucosal cells was detected by flowcytometry. Structural changes were assessed histologically, while autophagic and apoptotic changes of gastric mucosa were observed by transmission electron microscopy. ResultsCGA exhibited a dose-dependent gastroprotective effect by reversing IND-induced accumulation of autophagic vacuoles, significant reduction in beclin-1, LC3-II/LC3-I, and p62 levels, and down-regulation of p-Akt/p-mTOR expression. CGA100 also restored normal autolysosomal function by modulation of cathepsin-D levels. Furthermore, pretreatment with CGA100 was significantly associated with an increase in antiapoptotic protein Bcl-2 along with a decrease in proapoptotic Bax and caspase-3 proteins in such a way that impairs IND-induced apoptosis. This was confirmed by CGA-induced significant decrease in annexin V+ cells. ConclusionsThe natural compound CGA offers a novel gastroprotective intervention against IND-induced GU through restoration of normal autophagic flux, impairment of apoptosis in a crosstalk mechanism mediated by Akt/mTOR pathway reactivation, and alleviation of IND-induced lysosomal dysfunction.

Protective and therapeutic effects of the flavonoid "pinocembrin" in indomethacin-induced acute gastric ulcer in rats: impact of anti-oxidant, anti-inflammatory, and anti-apoptotic mechanisms.

Peptic ulcer including gastric and duodenal ulcers is a common gastro-intestinal disorder worldwide, associated with a significant mortality due to bleeding and perforation. Numerous efforts are being exerted to look for natural drugs that lack the potential side effects but still keep beneficial effects for treatment and/or prevention of gastric ulcer. Pinocembrin (PINO) is a natural flavonoid retaining anti-microbial, anti-oxidant, and anti-inflammatory activities. The present study was conducted to investigate the protective and therapeutic effects of PINO against indomethacin (INDO)-induced gastric ulcer in rats and the possible underlying mechanisms. PINO (25 and 50 mg/kg) promoted mucus secretion, decreased ulcer index, and inhibited histopathological changes induced by INDO. Further investigation of possible mechanisms showed that PINO significantly attenuated INDO-induced oxidative and inflammatory responses in both doses when administrated before or after ulcer induction. PINO downregulated mRNA expression level of p38-mitogen-activated protein kinase (p38-MAPK) which subsequently inhibited NF-κB activation and inflammatory cytokine release including tumor necrosis factor-α (TNF-α) and interleukin-1beta (IL-1β). Additionally, PINO inhibited apoptotic activity which was confirmed by downregulation of caspase-3 transcription. The current results demonstrated the promising therapeutic activity of PINO against INDO-induced gastric ulcer due to-at least partly-its anti-oxidant, anti-inflammatory, and anti-apoptotic effects.

Evaluation of the gastroprotective effects of Chihuahua propolis on indomethacin- induced gastric ulcers in mouse

The aim of this work was to evaluate the gastroprotective activity of a Mexican propolis on indomethacin-induced gastric ulcers in a mouse model. The following contents of the ethanolic extract of propolis of Chihuahua (EEPCh) were determined: antioxidant activity (SA50), total phenolic content (TPC), total flavonoid content (TFC), and chemical composition by HPLC-DAD and HPLC-MS, as well as acute toxicity by OECD Guideline 423. Gastric lesions were induced by intragastric indomethacin treatment in male ICR mice. As the positive control, omeprazole was administered, and three doses of EEPCh were evaluated (50, 150 and 300 mg/kg). Gastric mucosal injury, histological changes and mucosal content were evaluated by means of H&E and PAS staining. For homogenized gastric tissues, the following were evaluated: TBARS, MPO, and PGE2 levels; SOD and GPx antioxidant enzymatic activity; and the concentrations of the proinflammatory cytokines, TNF-α, IL-1β and IL-6. EEPCh had a significant SA50 of 41.55 µg/mL. The TPC of EEPCh was 860 mg GAE/g, and its TFC was 49.58 mg QE/g. Different phenolic compounds were identified in the extract and were not toxic. The EEPCh doses decreased mucosal damage and histological injuries, maintained the mucosal content and reduced the TBARS, MPO and concentrations of proinflammatory cytokines in gastric ulcer tissues. The 150 and 300 mg/kg doses increased the SOD activity and maintained the PGE2 content. Only the 300 mg/kg dose increased the GPx activity. The results of this study suggest that EEPCh displays gastroprotective effects by means of its antioxidant activity and anti-inflammatory effects and promotes ulcer protection through the maintenance of mucosal content and PGE2 levels.

Bioactivities of Pachypodium Lamerei Drake, Family Apocynaceae, Cultivated in Egypt

Aims: The current study estimated the anti-inflammatory, anti-pyretic, gastroprotective and antihyperglycemic activities in various rat models of total methanol extracts (TMEs) of different plant parts; mixture of leaves & stems (MLS) and subterranean organs (SO) and different fractions of TME of MLS of Pachypodium lamerei Drake. Additionally, we evaluated the median lethal dose (LD50) of TME of MLS. Place and Duration of Study: The study was carried out for nine months in 2012 in the Department of Pharmacology, Faculty of Medicine and the Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia, Egypt. Methodology: The preliminary phytochemical screening of TMEs of both MLS and SO of P. lamerei was carried out to determine secondary metabolites in the extracts. The TMEs of both MLS and SO and different fractions of TME of MLS of P. lamerei were used in the current biological study. The pharmacological activities, such as anti-inflammatory, anti-pyretic, gastroprotective, anti-hyperglycemic effects and LD50 were determined in male albino rats using various models. Results: The phytochemical screening of TMEs of both MLS and SO of P. lamerei contained carbohydrates and/or glycosides, unsaturated sterols and/or triterpenes, flavonoids, saponins and tannins. While, the biological activities are summarized as follows; in the carrageenan-induced paw edema method, TME of MLS had the highest anti-inflammatory activity (***P<0.001), whereas in the yeast-induced pyrexia method, the highest anti-pyretic effect was exerted by TME of SO (***P<0.001). Furthermore, in indomethacin-induced gastric ulcer, TME of SO exerted the most potent gastric protection. Moreover, in the alloxan-induced diabetes method, the most active extract was again TME of SO (***P<0.001). Finally, no toxicological symptoms of TME of MLS of P. lamerei were observed in graded single doses up to 5 gm/kg, during 24 hrs follow-up. Conclusion: From the aforementioned results, P. lamerei proved to be a promising candidate to be used in the development of various pharmaceutical herbal drugs viz., anti-inflammatory, antipyretic, gastroprotective, anti-hyperglycemic activities, since it exhibited a wide margin of safety.

Gastro-Protective Effects of Albizia anthelmintica Leaf Extract on Indomethacin-Induced Gastric Ulcer in Wistar Rats: In Silico and In Vivo Studies.

We have previously reported that the leaf extract of Albizia anthelmintica exhibited substantial antioxidant, anti-inflammatory, analgesic, and antipyretic properties in vivo. We also comprehensively characterized the active phytoconstituents and found several flavonoids and galloyl glucosides derivatives. In the current work, we explored the gastroprotective effects of the leaf extract in an indomethacin-induced ulcer model and the mechanisms involved. The rats being pretreated with the tested extract (100 and 200 mg kg−1) significantly prevented gastric lesions by 87.4% and 92.3%, respectively, and they had no structural derangements in the gastric mucosa. The extract significantly reduced the elevated levels of IKκB, NF-κB, TNF-α, IL-6, iNOS, and lipid peroxidation; increased the reduced level of glutathione peroxidase (GPx) activity; and reduced glutathione (GSH) in the indomethacin-induced ulcer model. The protective activities of the extract were similar in most aspects to those exerted by the known anti-ulcer drug famotidine. These activities might be attributed to the anti-inflammatory and antioxidant activities, and the reduction of iNOS levels. In conclusion, Albizia anthelmintica is a potential candidate for management of gastric ulcers with antioxidant properties.

Analgesic, anti-inflammatory and anti-ulcer properties of Thai Perilla frutescence fruit oil in animals.

Perilla frutescens fruit oil (PFO) is rich in α-linolenic acid (ALA) and exhibits biological activities. We aimed to investigate analgesic, anti-inflammatory and anti-ulcer activities of PFO and PFO-supplemented soybean milk (PFO-SM) in animal models. Analgesic activity was assessed in acetic acid-induced writhing in mice, while anti-inflammatory activity was performed in ethyl phenylpropiolate (EPP)-induced ear edema and carrageenan-induced hind paw edema in rats. Anti-ulcer effects were conducted in water immersion stress, HCl/ethanol and indomethacin-induced gastric ulcer in rats. Distinctly, PFO, containing 6.96 mg ALA and 2.61 mg LA equivalence/g, did not induce acute toxicity (LD50 > 10 mL/kg) in mice. PFO (2.5 and 5 mL/kg) and PFO-SM (0.05 mL PFO equivalence/kg) inhibited incidences of writhing (16.8, 18.0 and 32.3%, respectively) in acetic acid-induced mice. In addition, topical applications of PFO (0.1 and 1 mL/ear) significantly inhibited EPP-induced ear edema (59.3 and 65.7%, respectively) in rats, while PFO-SM slightly inhibited ear edema (25.9%). However, PFO and PFO-SM did not inhibit carrageenan-induced hind paw edema in rats. Indeed, PFO (2.5 and 5 mL/kg) significantly inhibited gastric ulcers in rats that induced by water immersion stress (92.4 and 96.6%, respectively), HCl/ethanol (74.8 and 73.3%, respectively) and indomethacin (68.8 and 88.9%, respectively), while PFO-SM did not. PFO displayed potent analgesic, anti-inflammatory and anti-ulcer properties, while PFO-SM exerted only analgesic properties. Thus, Thai PFO and its functional drink offer potential benefits in treatment of analgesic, inflammatory diseases and gastric ulcer.

Gastroprotective Effects of Methanolic Leaves and Stem Extracts of Sphagneticola trilobata on Indomethacin-Induced Gastric Ulcer in Rats

The medicinal plant Sphagneticola trilobata native to South America is used in local folk medicine to treat inflammation and analgesics. In present study, gastroprotective effects of methanolic extracts of S. trilobata leaves and stem were investigated in indomethacin-induced gastric ulcers in rats at doses of 200 mg/kg for leave extract and 350 mg/kg for stem extract. Indomethacin produced stomach ulcers and increased neutrophil percentage and MDA levels compared to the control group (p &lt; 0.001). Co-administration of indomethacin and omeprazole, methanolic extracts of leaves (200 mg/kg) (p &lt; 0.001) and methanolic extracts (350 mg/kg) (p &lt; 0.05) of stem compared to indomethacin group to ulcers was low (p &lt; 0.001). Methanolic extracts (200 mg/kg) of leaves and methanolic extracts (350 mg/kg) of stem reduced MDA levels (p &lt; 0.001). Methanolic extracts (200 mg/kg) of leaves and methanolic extracts (350 mg/kg) of the stem significantly decreased neutrophil percentage compared to indomethacin group (p &lt; 0.001). The results suggest that the methanolic extracts of Sphagneticola trilobata leaves and stem have a protective effect on indomethacin-induced gastric ulcers.

Anti-ulcerogenic effect of methanol fraction of Ocimum gratissimum leaves extract and honey on indomethacin-induced gastric ulcer in rats

ABSTRACT Ocimum gratissimum (Og), a medicinal plant, and honey (H), a natural sweetener usually produced by bees, have historic importance in managing several ailments. This study aims at unraveling the anti-ulcerogenic effect of methanol leaves fraction (MEF) of Og and H on indomethacin-induced gastric ulcer in male rats. Crude methanol extract was partitioned between hexane, chloroform, ethylacetate and methanol successively using vacuum liquid chromatography. The anti-ulcerogenic effect of MEF of Og (100 and 400 mg/kg), honey (2.5 g/kg) and their combination was determined using indomethacin-induced gastric ulcer model. Gastric acidity, antioxidant assays and histopathology were conducted via titrimetric, spectrophotometric, H&E stain with microscopy methods respectively. Significant difference (P < 0.05) existed in ulcer score and gastric pH in all groups except MEF pre-treated relative to control. Significant increase and decrease existed in MDA level in untreated and pre-treated groups successively compared to control. CAT activity displayed no significant difference in 400 mg/kgMEF and 400 mg/kg/2.5 g/kgH proportionate to control. GST activity showed significant elevation in pre-treated groups compared to control. Meanwhile, GPx activity increased in 400 mg/kg MEF and 400 mg/kgMEF/2.5 g/kgH relative to control. There was no significant difference in TSH status in the pre-treated groups relative to control. Mild inflammatory cellular infiltration in the sub-mucosal layers in pre-treated groups occurred. The data suggests MEF effectively prevented ulcer better than fortification with honey and honey used singly.

Mechanisms underlying the healing potentials of the methanol extract of Chasmanthera dependens stem on indomethacin-induced gastric ulcer

ABSTRACT Chasmanthera dependens stem is used in African traditional medicine as a remedy for various maladies; however, scientific evidence to validate its uses in gastric ulcer healing is lacking. This study investigated the mechanisms underlying the healing potentials of the methanol extract of C. dependens stem (MECD) on the indomethacin-induced gastric ulcer. Forty male Wistar rats at 8 weeks old were used in this study and divided into five groups (n = 8). Group 1: control group, group 2: indomethacin alone (ulcerated untreated), group 3: ulcerated + 200 mg/kg MECD, group 4: ulcerated + 400 mg/kg MECD and group 5: ulcerated + 50 mg/kg cimetidine. Treatment with either MECD or cimetidine was once daily for 14 days after ulcer induction. Histological gastric injuries, antioxidant, inflammatory and apoptotic markers were evaluated. The results obtained revealed gastric mucosa damage as evident by marked histologic changes, increased ulcer score, ulcer index, lipid peroxidation, Tumor necrosis-alpha (TNF-α), Interleukin-1β (IL-1β), Cytochrome c (Cyt-c), Caspase-9 (Casp-9), Caspase-3 (Casp-3) and a number of apoptotic nuclei and significant decreased gastric antioxidant status, prostaglandin-E2 (PGE2) and vascular endothelia growth factor (VEGF) levels at p< 0.01. But MECD or cimetidine treatments significantly heal the ulcer and remarkably improved the biochemical parameters.

Evaluation of the effect of hydroalcoholic and flavonoid-enriched extracts of Dracocephalum kotschyi on indomethacin-induced gastric ulcer in rats.

Background and purpose:Dracocephalum kotschyi (Zaringiah) is a fragrant wild medicinal plant found in Iran. Traditionally, it is used for the treatment of rheumatism, asthma, and gastrointestinal ailments. So far no investigation has been done on the beneficial or side effects of D. kotschyi on peptic ulcer. Therefore, this research was performed to find out whether D. kotschyi extract would induce peptic ulcer or could alleviate existing peptic ulcer.Experimental approach:Effect of hydroalcoholic (DKHE) and flavonoid extracts (DKFE) of D. kotschyi were determined in normal or indomethacin-induced gastric ulcer rats (n = 6) and compared with the vehicle and ranitidine treated controls. All the treatments were carried out orally and 24 h later the stomach mucus was visually examined for peptic ulcers. A section of the stomach was taken for microscopic histopathological examinations while another section of the stomach was used for measurement of myeloperoxidase (MPO) and malondialdehyde (MDA) activities.Findings/Results:Oral administration of the DKHE and DKFE alone, did not cause any sign of gastric ulcer induction. The D. kotschyi extracts not only didn’t aggravate the induced ulcer but also significantly prevented the severity of gastric ulcer induction by indomethacin. In addition, DKHE and DKFE inhibited MPO (up to 58.2%) and MDA (up to 44.2%) activities indicating their anti-inflammatory and antioxidant potential action on the stomach-induced ulcer.Conclusion and implication:Usage of D. kotschyi extracts is not associated with gastric ulcer induction and its co-administration with NSAIDs would be beneficial for controlling both the inflammation and preventing gastric ulcer in diseases such as rheumatism.

Protective effects of phloretin and phloridzin on indomethacin-induced gastric ulcers in mice: characterization of potential molecular mechanisms

Purpose: We aimed to examine the potential protective effects of phloretin and phloridzin in indomethacin induced ulcer model in mice.&#x0D; Materials and Methods: In total 54 female Balb/C mice were separated into nine groups. Famotidine was used as standard antiulcer agent. The phloretin and phloridzin was given at the doses of 50 and 100 mg/kg as a pre-treatment. After experimental procedures stomach tissue oxidative parameters (SOD, GSH and MDA), inflammatory cytokine TNF-α, and COX1 and COX2 mRNA expressions were analyzed. In addition, to clarify antiulcer effect mechanism of phloretin and phloridzin, numerical densities of ulcerative areas were analyzed.&#x0D; Results: Phloretin and phloridzin inhibited indomethacin-induced ulcer formation in dose dependent manner. Tissue inflammation and oxidative stress were increased after the indomethacin administration. Phloretin and phloridzin treatment normalized all parameters compared to indomethacin treated group. After the treatments, SOD activities and GSH levels were increased while MDA levels were decreased. Phloretin and phloridzin treatments decreased TNF-α, COX1 and COX2 mRNA expressions.&#x0D; Conclusion: Our results showed that phloretin and phloridzin may be an alternative treatment for peptic ulcer disease due to their potential regulatory effects against oxidative stress and inflammation.

The effect of metformin on indomethacin-induced gastric ulcer: Involvement of nitric oxide/Rho kinase pathway

Gastric ulcer is a very common disease that represent an economic burden. Non-steroidal anti-inflammatory drugs induce ulcer in old patients and in patients with comorbidities. Indomethacin is widely used to induce gastric ulcer in animal models. Diabetic patients are highly susceptible to develop gastric ulcer. Metformin, the first line medication for the treatment of type II diabetes melilites that have many off label uses in non-diabetic patients, has been recently reported to have anti-inflammatory activities. Therefore, this research was conducted to assess the possible healing effects of metformin on gastric ulcers induced by indomethacin in rats. Indomethacin (48 mg/kg) single dose increased stomach acidity, ulcer index and induced histopathological changes. Indomethacin also decreased mucin levels and increased the activity of tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB), Rho-associated protein kinas-1 (ROCK-1) and decreased the levels of the protective nitric oxide (NO). After the induction of ulcer, rats were treated by omeprazole (30 mg/kg) or metformin (50, 100 or 200 mg/kg). Omeprazole and metformin were found to decrease stomach acidity and ulcer index, restored the histological features and increased mucin levels. Both also decreased the levels of NF-κB, TNF-α, ROCK-1 and increased NO. Metformin exerted ulcer healing effects comparable to that of omeprazole. This can be attributed, at least partly, to its anti-inflammatory activity and increasing NO levels.

Gastroprotective effects of both aqueous and ethanolic extracts of Lemon verbena leaves against indomethacin-induced gastric ulcer in rats.

Objective(s):Regarding Lemon verbena gastroprotective effects, we investigated the protective effects of Lemon verbena extracts on reducing gastric ulcer induced by indomethacin.Materials and Methods:Rats received aqueous and ethanolic extracts of Lemon verbena (50, 100, and 200 mg/kg), zileuton (100 mg/kg), montelukast (10 mg/kg), or 1% Tween 80 in presence or absence of indomethacin (100 mg/kg).Results:Indomethacin produced stomach ulcer and increased neutrophils percentage and MDA level compared with the control group (P<0.001). Co-administration of indomethacin and zileuton, montelukast and ethanolic (200 mg/kg) (P<0.001), aqueous extract (200 mg/kg) (P<0.05) reduced ulcer compared with the indomethacin group (P<0.001). Ethanolic extracts (100 and 200 mg/kg) and aqueous extract (200 mg/kg) reduced the MDA level (P<0.001). Ethanolic (50, 100, and 200 mg/kg) and aqueous extracts (200 mg/kg) significantly decreased neutrophils percentage compared with the indomethacin group (P<0.001).Conclusion:Aqueous and particularly ethanolic extracts of Lemon verbena have protective effects on indomethacin-induced gastric ulcers.

Role of Daucus carota in Enhancing Antiulcer Profile of Pantoprazole in Experimental Animals.

The carrot plant (Daucus carota) and its components are traditionally reported for the management of gastric ulcers. This study was performed to evaluate the role of carrot when administered concurrently with a conventional antiulcer treatment, pantoprazole, in alleviating gastric and duodenal ulcers in female experimental animals. The study involved standard animal models to determine the ulcer preventive effect using pylorus ligation, ethanol, and stress induced acute gastric ulcer models and duodenal ulcer models involving cysteamine. Acetic acid-induced chronic gastric ulcer and indomethacin-induced gastric ulcer models were used to evaluate the ulcer healing effect. Carrot fruit (500 mg/kg) and its co-administration with pantoprazole produced significant protection in an ethanol- and stress-induced acute gastric ulcer and cysteamine-induced duodenal ulcer. The healing of the acetic acid-induced chronic gastric ulcer was also augmented with this combination. Both total proteins and mucin contents were significantly increased in indomethacin-induced gastric ulcers. Similarly, in pylorus ligation, the pepsin content of gastric juice, total acidity, and free acidity were reduced. Overall, both ulcer preventive effects and ulcer healing properties of the pantoprazole were significantly enhanced in animals who received the co-administration of carrot fruit (500 mg/kg).

Free Radical Production and Production Mechanism in the Early and Advanced Stages of Gastrointestinal Lesions

Disruption of redox balance due to the overproduction of free radicals and reactive oxygen species (ROS) could cause protein denaturation, lipid peroxidation, and DNA mutation. These lead to an induction of gastrointestinal diseases such as gastric ulcers induced by long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs) and ulcerative colitis. Magnetic resonance technique, which is non-invasive and free of radiation exposure, is a promising tool for evaluating redox status in the living body. This study investigated ROS production in rats with gastric ulcers induced by a typical NSAIDs indomethacin using in vivo ESR/spin probe technique. The ESR signal intensity of membrane-permeable nitroxyl probe in the indomethacin group showed enhanced decay compared with the vehicle group, but the enhancement was not observed in the presence of a membrane-permeable ROS scavenger, suggesting the intracellular ROS production. The imaging analysis using Overhauser-enhanced MRI (OMRI) with dual probes labeled with 14N and 15N enabled visualization of ROS production in the glandular stomach of rat with indomethacin-induced gastric ulcers. The intracellular ROS production in the distal and proximal colon in the initiation stage and intra- and extra-cellular ROS production of the advanced stage of colitis induced by dextran sodium sulfate (DSS) using the OMRI/dual-probe technique was observed. Furthermore, nitration of src homology protein tyrosine phosphatase 2 in macrophages might be involved in the activation of Toll-like receptor 4 and NF-κB, inducing infiltration of activated neutrophils into colonic mucosa to produce ROS in DSS-induced colitis mice.