Indomethacin-induced Gastric Damage Research Articles

Dietary Walnuts Prevented Indomethacin-Induced Gastric Damage via AP-1 Transcribed 15-PGDH, Nrf2-Mediated HO-1, and n-3 PUFA-Derived Resolvin E1.

Non-steroidal anti-inflammatory drugs (NSAIDs), the most highly prescribed drugs in the world for the treatment of pain, inflammation, and fever, cause gastric mucosal damage, including ulcers, directly or indirectly, by which the development of GI-safer (-sparing) NSAIDs relates to unmet medical needs. This study aimed to document the preventive effects of walnut polyphenol extracts (WPEs) against NSAID-induced gastric damage along with the molecular mechanisms. RGM-1 gastric mucosal cells were administered with indomethacin, and the expressions of the inflammatory mediators between indomethacin alone or a combination with WPEs were compared. The expressions of the inflammatory mediators, including COX-1 and COX-2, prostaglandin E2, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and antioxidant capacity, were analyzed by Western blot analysis, RT-PCR, and ELISA, respectively. HO-1, Nrf-2, and keap1 were investigated. The in vivo animal models were followed with in vitro investigations. The NSAIDs increased the expression of COX-2 and decreased COX-1 and 15-PGDH, but the WPEs significantly attenuated the NSAID-induced COX-2 expression. Interestingly, the WPEs induced the expression of 15-PGDH. By using the deletion constructs of the 15-PGDH promoter, we found that c-Jun is the most essential determinant of the WPE-induced up-regulation of 15-PGDH expression. We confirmed that the knockdown of c-Jun abolished the ability of the WPEs to up-regulate the 15-PGDH expression. In addition, the WPEs significantly increased the HO-1 expression. The WPEs increased the nuclear translocation of Nrf2 by Keap-1 degradation, and silencing Nrf2 markedly reduced the WPE-induced HO-1 expression. We found that the WPE-induced HO-1 up-regulation was attenuated in the cells harboring the mutant Keap1, in which the cysteine 151 residue was replaced by serine. These in vitro findings were exactly validated in indomethacin-induced gastric rat models. Daily walnut intake can be a promising nutritional supplement providing potent anti-inflammatory, antioxidative, and mucosa-protective effects against NSAID-induced GI damage.

Probiotic bacteria protect against indomethacin-induced gastric ulcers through modulation of oxidative stress, inflammation, and apoptosis.

Indomethacin is an anti-inflammatory drug that causes ulcers on the gastric mucosa due to its use. Probiotic bacteria are live microorganisms, and it has been stated by various studies that these bacteria have antioxidant and anti-inflammatory effects. In this study, we investigated the possible protective effect of various types of probiotic bacteria (Lactobacillus rhamnosus, Lactobacillus fermentum, and Lactobacillus brevis) against acute gastric mucosal damage caused by indomethacin. Control group - Physiological saline was administered daily for 10 days. Indo group-Physiological saline was administered daily for 10 days. Ranitidine + Indo group 5mg/kg ranitidine dose was administered daily for 5 days. On day 11, a single dose of 100mg/kg of indomethacin was given to the same group. Probiotic + Indo group 1ml/kg of oral probiotic bacteria was administered daily for 10 days. On day 11, a single 100mg/kg dose of indomethacin was given. After the application, the rats were anesthetized with ketamine xylazine, killed under appropriate conditions, the abdominal cavity was opened and the stomach tissues were removed. The obtained gastric tissues were used in the biochemical and histopathological analyses discussed below. All data were statistically evaluated by one-way ANOVA using SPSS 20.00, followed by Duncan Post hoc test. The data were expressed as mean ± SD. P < 0.05 was considered statistically significant. As a result, the administration of indomethacin caused gastric damage, stimulating oxidative stress, inflammation, and apoptosis. We found that the use of probiotic bacteria reduces oxidative stress (TOC), increases the activity of antioxidant enzymes (TAC), suppresses inflammation (IL-6 and Tnf-α), and inhibits apoptosis (Bax and Bcl-2) (P < 0.05). Probiotic treatment can mitigate gastric damage and apoptosis caused by indomethacin-induced gastric damage in rats. Probiotic also enhances the restoration of biochemical oxidative enzymes as it has anti-inflammatory, antioxidant, and antiapoptotic properties.

Syringic acid guards against indomethacin-induced gastric ulcer by alleviating inflammation, oxidative stress and apoptosis

ABSTRACT The purpose of this study was to evaluate the effects of syringic acid, an anti-oxidant, on indomethacin induced gastric ulcers in rats. Experimental groups were control, ulcer, ulcer treated with 20 mg/kg esomeprazole (a proton pump inhibitor that reduces acid secretion), and ulcer treated with 100 mg/kg syringic acid. Rats were pretreated with esomeprazole or syringic acid two weeks before ulcer induction. Our histopathological observations showed that either syringic acid or esomeprazole attenuated the severity of gastric mucosal damage. Moreover, syringic acid and esomeprazole pretreatments alleviated indomethacin-induced damage by regulating oxidative stress, inflammatory response, the level of transforming growth factor-β (TGF-β), expressions of COX and prostaglandin E2, cell proliferation, apoptosis and regulation of the NF-κB signaling pathway. We conclude that either esomeprazole or syringic acid administration protected the gastric mucosa from harmful effects of indomethacin. Syringic acid might, therefore be a potential therapeutic agent for preventing and treating indomethacin-induced gastric damage.

Gastroprotective effect of Vien Khoi Tim capsules on indomethacin-induced gastric ulcers in rats

Available anti-ulcer drugs unveil partial effectiveness and numerous adverse reactions. Plants offer an alternative strategy in the search for new drugs in the therapy and prevention of peptic ulceration. The present study investigated the possible protective effect of the herbal formulation Vien Khoi Tim (VKT) on indomethacin-induced gastric mucosal damage in rats. VKT was tested at two doses (1.44 &amp; 0.48 capsules/kg/d po) ten days before the indomethacin single-dose challenge (40 mg/kg po). Animals were sacrificed six hours after indomethacin administration, and gastric tissues were collected for gross observation and histopathological analyses. The results revealed that the administration of indomethacin caused evident gastric mucosal damage with morphological and histological manifestations. VKT pretreatment tended to avert the rise in lesion numbers, reduce the ulcer index, and improve the severity of bleeding streaks and epithelial sloughing in gastric mucosa on the macroscopic examination compared to the model group. It is worth noting that no ulcerative lesions were observed in the gastric tissues of rats receiving VKT upon microscopic examination. Our results indicated that Vien Khoi Tim capsules might possess a protective role against indomethacin-induced gastric ulcers. Additional research is needed to better understand the mechanism by which Vien Khoi Tim capsules exert their gastroprotective effect.

Freshwater Clam Extract Attenuates Indomethacin-Induced Gastric Damage In Vitro and In Vivo.

Contemporary pharmacological studies have reported that freshwater clam (Corbicula fluminea) can provide a broad spectrum of bioactivities, including antioxidant, anticancer, antihypertensive, hepatoprotective, and hypocholesterolemic effects. The aim of this study was to evaluate the gastroprotective effects of water extract of freshwater clam (WEC) on indomethacin (IND)-induced gastric mucosal cell damage in vitro and gastric ulcer in vivo. The cell viability of rat gastric mucosa RGM-1 cells was markedly decreased by 0.8 mM of IND treatment, and pre-treated with various concentration of WEC significantly restored IND-induced cell damage in a dose-dependent manner. WEC also significantly attenuated the elevated reactive oxygen species (ROS) levels, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, and nuclear factor-κB (NF-κB) p65 nuclear translocation induced by IND. In the in vivo study, IND caused severe gastric ulcer in Wistar rats, while WEC pretreatment effectively reduced the ulcer area and edema in the submucosa. We found that WEC significantly restored glutathione (GSH) content in gastric mucosa in a dose-dependent manner (p < 0.05). The reduction of prostaglandin E2 (PGE2) caused by IND was also improved with higher doses of WEC administration. Moreover, the overexpression of COX-2, iNOS, and tumor necrosis factor-α (TNF-α) proteins in gastric mucosa was downregulated by administration of WEC. Consequently, WEC can be used as a potential nutritional supplement to improve NSAIDs-caused gastric mucosal lesions.

Ulcero-Protective Potential of Ethyl Acetate Fractions of Persea americana Seed and Bryophyllum pinnatum Leaf Binary Combinations in Indomethacin Induced Gastric Ulcer

Aims: This study was aimed at investigating the protective potential of ethyl acetate fractions of Persea americana (PA) seed and Bryophyllum pinnatum (BP) leaf binary combinations against indomethacin-induced gastric ulcers.&#x0D; Methodology: Fifty (50) male Wistar rats were used in this study; they were assigned into 10 groups of five animals each and respective groups received a standard rat diet and drinking water ad libitum. The groups were group 1 (normal control group (NC)), group 2 (ulcer control (UC)), group 3 (Omeprazole, 20mgkg-1 (OMEP)), group 4 (PA) and group 5 (BP). Groups receiving binary combinations were group 6 (PA + BP, 1:1), group 7 (PA + BP, 1:2), group 8 (PA + BP, 1:3), group 9 (PA + BP, 2:1), group 10 (PA + BP, 3:1) each group was pre-treated with 400 mgKg-1 body weight/day of respective fraction or binary mixture by intubation for 21 days. On the 22nd day after overnight fasting, a gastric ulcer was induced with indomethacin (30mg/kg body weight) by intubation in a single dose. Ulcer markers and histopathology of stomach tissues were measured using standard methods.&#x0D; Results: The present study revealed that the ethyl acetate fraction of the plants PA seeds and BP leaf showed potent gastric tissue protective effects. Analysis of gastric changes indicated a significant (P&lt;0.05) reduction in ulcer index, gastric acid output, gastric mucus content and pepsin activity of ulcerated rats pretreated with PA and BP fractions. The effect of the binary combinations was significantly (p&lt;0.05) higher than single plant fractions. The protective effect of the fractions was in the order OMEP &gt; PA+BP (3:1) &gt; PA+BP (2:1) &gt; PA+BP (1:1), &gt; PA+BP (1:2) &gt; PA+BP (1:3) &gt; PA &gt; BP. The observed ulcero-protective effect of the binary combinations of P. americana seed and B. pinnatum leaf may be attributed to the synergy of the phytochemicals contained in the fractions.&#x0D; Conclusion: These findings suggest that P. americana and B. pinnatum ethyl acetate fraction combination favorably protect against indomethacin-induced gastric mucosal oxidative damage, reducing ulcer index, gastric acid output, gastric mucus content and pepsin activity. The ethyl acetate fractions exhibited a dose-dependent inhibition of ulcer formation in indomethacin gastric ulcer model.

The effects of dragon fruit (Hylocereus polyrhizus) extract on indomethacin-induced stomach ulcer in rats.

The aim of this study was to investigate the effects of red dragon fruit (Hylocereus polyrhizus) extract (DFE) on the stomach in ulcer model induced by indomethacin in rats. Effects of DFE were evaluated in indomethacin-induced gastric damage model on Sprague-Dawley rats. Experimental model: all rats were fasted for 24 h. At the end of this period, DFE was administered to the ulcer-induced groups. One hour after this application, a dose of 25 mg/kg of indomethacin was applied by oral gavage to all groups except the HEALTHY and DFE1000 groups. Six hours after indomethacin administration, the rats were euthanized with high-dose anesthesia and the experiment was terminated. Macroscopic and microscopic analyses for investigating ulcerative area, molecular and biochemical analyses for oxidative damages investigation and molecular analyses for the effect mechanism of indomethacin and DFE were conducted on stomach tissues in the study. While oxidative stress-associated markers such as MDA, BAX, and Caspase 3 increased dramatically in the indomethacin group, GSH antioxidant levels decreased. It was observed that these parameters were significantly improved in DFE 500 mg/kg and DFE 1000 mg/kg groups compared to ulcer group, and the results of especially DFE 1000 mg/kg group were similar to famotidine group. We observed that our histopathological findings also supported all our other findings. Dragon fruit extract was protected against indomethacin-induced ulcer damage by decreased MDA levels, increased GSH levels, and inhibition of Caspase 3, BAX, and Cox-2, and activation of Cox-1. PRACTICAL APPLICATIONS: People of all ages around the world suffer from gastric ulcer which is one of the most common gastrointestinal ailments. The etiological factors of the disease are using of cigarette and alcohol, nutritional deficiencies, infections, and using non-steroidal anti-inflammatory drugs which use frequent and indiscriminate. Indomethacin is one of the NSAIDs and is commonly preferred to induce ulcer modeling in rats due to its gastric toxicity potential. Current anti-ulcer drugs have many serious side effects. Patients who suffered from gastric ulcer tend to discontinue the drug because of side effects. Therefore, patients need new agents that are non-toxic, have few side effects, and are easily accessible anti-ulcer drugs. Dragon fruit, as a medicinal herb, is highly valuable and widely used in traditional medicine, and may provide gastroprotective activity. Studies have shown that H. polyrhizus has antioxidant activities. We consider the effects of dragon fruit extract (DFE) to be a therapeutic drug for an indomethacin-induced ulcer model.

Gastroprotective effect of topiramate on indomethacin-induced peptic ulcer in rats: Biochemical and histological analyses.

Topiramate is an anticonvulsant drug effective against a wide range of seizures and epilepsies. The present study was conducted to investigate the possible protective effect of topiramate on indomethacin-induced gastric mucosal damage in rats. The animals were randomly distributed into four experimental groups with 10 animals in each group. Group 1 was the control group received vehicle only (DMSO at 1:4 (w/v)), group 2 was the model group received indomethacin (50 mg/kg; i.p.), and groups 3 and 4 received topiramate (100 mg/kg; i.p.) and ranitidine (100 mg/kg; i.p.), respectively, 1h before indomethacin (50 mg/kg; i.p.). The efficacy of topiramate was compared with ranitidine. Animals were euthanized 4h after indomethacin administration, and gastric tissues were collected for macroscopical, histopathological, and biochemical analyses. The mucosal lesions in the gastric corpus were evaluated by pathological examinations. The results revealed that the administration of indomethacin caused evident gastric mucosal damage with morphological and histological manifestation, whereas topiramate pretreatment extensively ameliorated the gastric injuries. Topiramate pretreatment also reduced the contents of tissue malonaldehyde, enhanced ferric reducing antioxidant power value and glutathione levels, and increased the activity of superoxide dismutase, catalase, and glutathione peroxidase in gastric mucosa compared to the model group. Our results indicate that topiramate might possess a protective role against indomethacin-induced gastric ulcers by inhibition of oxidative stress in gastric tissue.

Effects of Rhodiola rosea on indomethacin-induced gastric injury

Objective: The objective of the present study was to evaluate the effects of Rhodiola rosea in the indomethacin-induced ulcer model in rats and to clarify the underlying mechanisms of action.&#x0D; Methods: Rats in treatment groups were treated with Rhodiola rosea (RR) 14 days. Peptic ulcer was induced by indomethacin (IND) injection (100 mg/kg, p.o.). The groups (n = 6) were designed as; Group I (control); Group II (IND): After 24h of food starvation, rats were given only 100 mg/kg IND by oral gavage to induce gastric mucosal injury. Group III (ESO): Rats were pretreated with 20 mg/kg of ESO for 14 consecutive days by oral gavage. Group IV (RR): Rats were pretreated with 500 mg/kg RR for 14 consecutive days with oral gavage.&#x0D; Results: Rhodiola rosea effectively alleviated indomethacin-induced ulcer via reduction in oxidative stress (decreased MDA and increased SOD, and GSH). Moreover, Rhodiola rosea alleviated indomethacin-induced damage by regulating expressions of COX enzymes, prostaglandin E2, proliferating cell nuclear antigen (PCNA), cell proliferation, apoptosis and regulated the NF-κB signaling pathway. Rhodiola rosea also attenuated inflammatory injury by suppressing TNF-𝛼𝛼, IL-1β, and NF-κB. The caspase-3 expression was also down-regulated in stomach tissues.&#x0D; Conclusions: In conclusion, Rhodiola rosea protected the gastric mucosa from harmful effects of indomethacin and as a natural medicinal herb, Rhodiola rosea might be a potential therapeutic agent for preventing and treating indomethacin-induced gastric damage.

Protective effects of perindopril against indomethacin-induced gastric mucosal damage through modulation of DDAH-1/ADMA and ACE-2/ANG-(1-7) signaling pathways

Indomethacin is a widely used nonsteroidal anti-inflammatory drug; however, its clinical utility is accompanied by serious adverse reactions including peptic ulcers. The current study aims to investigate the protective potential of perindopril against indomethacin-induced gastric injury in rats. Perindopril (4 mg/kg) was administered orally for 7 days and indomethacin (60 mg/kg, single oral dose) was administered on the 7th day, 1 h after perindopril administration. Pantoprazole was used as a standard agent. Ulcer index (UI), preventive index ratio (PI), histopathological examination, oxidative stress, and inflammatory biomarkers were investigated. Perindopril significantly decreased UI while increased PI and counteracted histopathological aberrations induced by indomethacin. It alleviated indomethacin-induced oxidative stress by lowering NO while increasing GSH content and superoxide dismutase activity. Perindopril significantly downregulated TNF-α and asymmetric dimethylarginine (ADMA), while significantly upregulated COX-2, PGE-2, dimethylarginine dimethylaminohydrolase-1 (DDAH-1), ANG-(1-7), and ACE-2 expression. Together, these findings suggest the gastroprotective effects of perindopril through modulation of DDAH-1/ADMA and ACE-2/ANG-(1-7) signaling. HIGHLIGHTS Perindopril attenuated gastric histopathological damage. It increased GSH content and SOD activity while decreased NO content. It modulated gastric ADMA and DDAH-1 activity. It reduced TNF-α, while increased COX-2 and PGE-2 expression. It upregulated ACE-2 activity and ANG-(1-7) protein expression.

Effect of Single and Repeated Administration of Amitriptyline on Experimental Gastric Ulcer

Amitriptyline is an antidepressant drug widely used as analgesic in the management of chronic pain syndromes. It is also attracting the attention of researchers as an alternative agent for peptic ulcer management because studies have shown that most patients with peptic ulcer also suffer from depression. Thus, this study was conducted to investigate gastroprotective effects of single and repeated dose administration of amitriptyline against indomethacin-induced gastric injury in rats. Rats were randomly divided into three groups of eight rats/each. For 14 days, Group I (control) and Group II (single dose) received distilled water; Group III (repeated dose) received 10 mg/kg amitriptyline orally once daily. On day 15, Group I was given distilled water; Group II and III were given 10 mg/kg amitriptyline orally. Thirty minutes later, indomethacin (25 mg/kg) was administrated orally to all the groups. Six hours after indomethacin administration, animals were sacrificed under thiopental sodium anaesthesia, stomachs were rapidly removed, cut along the greater curvature and cleaned. The stomachs were macroscopically evaluated; total area of stomach and visible ulcerated areas were measured using millimeter square paper. Finally, the stomachs were fixed in 10% formalin for histopathologic valuation. Single dose administration of amitriptyline significantly reduced ulcer indexes and gastric erosions as compared to the control group.However, its role against inflammatory reactions such as necrosis, polymorphonuclear leucocyte infiltration, neutrophil and eosinophil reactions were statistically insignificant. On the other hand, repeated dose administration of amitriptilyine produced significant gastroprotective effects as observed from macroscopical and histopathological evaluation results. Moreover, there was also a significant difference in the gastroprotective effects between single and repeated dose of amitriptyline against indomethacin-induced gastric damage. In conclusion, the results of this study evealed that repeated dose administration of amitriptyline showed better gastroprotective effects compared to single dose amitriptyline administration and the control group.&#x0D; Keywords: amitriptyline, gastroprotective effects, indomethacin, histopathologic evaluation, rats

Gastroprotective Properties of Nanoemulsion of Ligusticum porteri Volatile Oil in Rats

The roots of Ligusticum porteri J.M. Coult. & Rose, Apiaceae, are used in Mexican traditional medicine for the treatment of gastrointestinal disorders. The dimeric phthalide (Z´)-diligustilide found in their organic extracts is associated with the gastroprotective properties. In this study, the gastroprotective effect of nanoemulsion of the volatile oil from the roots of L. porteri (at doses of 1, 3, 10, and 30 mg/kg) in the indomethacin-induced gastric damage model was tested, and nitric oxide (NO) and hydrogen sulfide (H2S) gastric levels were determinate. The volatile oil obtained by steam distillation (0.63% yield) contained 37 constituents, as assessed by GC-MS analysis, where the significant compounds were 4-phenyl-3-buten-2-ol (20.54%) and (Z)-3-butylidenephthalide (20.54%) that correspond to phthalide monomers. These results demonstrate that nanoemulsion of the volatile oil from L. porteri (at 10 and 30 mg/kg) shows a significant gastroprotective effect (72 and 92% respectively) against indomethacin-induced gastric damage, which is not different from the gastroprotective effect of omeprazole (69%) (p < 0.05). Furthermore, these doses of the nanoemulsion maintain the basal H2S gastric levels (209.70 ± 11.50 and 222.0 ± 5.30 nmol/g tissue) even in the presence of indomethacin. From these findings, we concluded that L. porteri volatile oil in nanoemulsion preparation might facilitate the gastroprotective action and it could serve as a future therapeutic approach for NSAID-related gastropathy.

Mechanistic evaluation of gastro-protective effects of KangFuXinYe on indomethacin-induced gastric damage in rats.

KangFuXinYe (KFX), the ethanol extract of the dried whole body of Periplaneta americana, is a well-known important Chinese medicine preparation that has been used to treat digestive diseases such as gastric ulcers for many years in China. However, its therapeutic effect and mechanism are not yet well understood. Thus, the aim of this study was to investigate the gastro-protective effects of KangFuXinYe (KFX) in indomethacin-induced gastric damage. Rats were randomly divided into six groups as follows: control, treated with indomethacin (35 mg·kg-1), different dosages of KFX (2.57, 5.14 and 10.28 mL·kg-1, respectively) plus indomethacin, and sucralfate (1.71 mL·kg-1) plus indomethacin. After treatment, rat serum, stomach and gastric homogenates were collected for biochemical tests and examination of histopathology firstly. Rat serum was further used for metabolomics analysis to research possible mechanisms. Our results showed that KFX treatment alleviated indomethacin-induced histopathologic damage in rat gastric mucosa. Meanwhile, its treatment significantly increased cyclooxygenase-1 (COX-1), prostaglandin E2 (PGE2) and epidermal growth factor (EGF) levels in rat serum and gastric mucosa. Moreover, KFX decreased cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) levels. Nine metabolites were identified which intensities significantly changed in gastric damage rats, including 5-hydroxyindoleacetic acid, indoxylsulfuric acid, indolelactic acid, 4-hydroxyindole, pantothenic acid, isobutyryl carnitine, 3-methyl-2-oxovaleric acid, sphingosine 1-phosphate, and indometacin. These metabolic deviations came to closer to normal levels after KFX intervention. The results indicate that KFX (10.28 mL·kg-1) exerts protective effects on indomethacin-induced gastric damage by possible mechanisms of action (regulating tryptophan metabolism, protecting the mitochondria, and adjusting lipid metabolism, and reducing excessive indomethacin).

Anti-ulcerogenic effect of osajin on indomethacin-induced gastric damage in rats

Ulcer is the most common undesirable result of using non-steroid anti-inflammatory drugs such as indomethacin. In the present study, osajin was experimentally used on indomethacin-induced gastric ulcer in rats. Osajin was purified from Maclura pomifera (Raf.) C. K. Schneid fruits by using the chromatographic methods. Thirty six rats were divided into six groups as follows: healthy (control), IND (indomethacin), RAN (ranitidine, 25 mg/kg), OSJ 100 (osajin, 100 mg/kg), OSJ 200 (200 mg/kg) and OSJ 400 (osajin, 400 mg/kg). Following a 24-h fasting, IND was administered to the treatment groups at a dose of 25 mg/kg. RAN and OSJ were given orally to rats following 5 min of IND administration. Then, gastric tissues were taken 6 h after the IND administration. Determination of the ulcer area, pathological evidence, and biochemical indices such as lipid peroxidation, superoxide dismutase, glutathione, and catalase were performed. IND generated diffuse ulcer areas, severe hyperaemia, oedema, necrotic epithelium, and mononuclear cell infiltration in the mucosa, and significantly increased lipid peroxidation while also decreasing the glutathione concentration, superoxide dismutase and catalase activities of the tissue. OSJ and RAN showed significant amelioration on ulcer area and biochemical indices. Therefore, OSJ may be potentially therapeutic for gastric ulcers.

Total triterpenoids from the fruits of Chaenomeles speciosa exerted gastroprotective activities on indomethacin-induced gastric damage via modulating microRNA-423-5p-mediated TFF/NAG-1 and apoptotic pathways.

Our previous studies have demonstrated that the total triterpenes from the fruits of Chaenomeles speciosa (CSTT) exhibit effective therapeutic effects on gastric ulcer patients and animals. The present aim is to further investigate the mechanisms involved. The results indicated that CSTT could ameliorate IND-induced gastric injury, which was related to promoting IND-damaged GES-1 cell proliferation and migration, improving the IND-damaged rat GBF, ulcer area, inhibition rate and pathologic changes of gastric mucous tissue, increasing the amount of adhered gastric mucus, attenuating the volume and total acidity of the gastric effluents, and augmenting the gastric pH; further studies showed that CSTT obviously downregulated miR-423-5p mRNA, NAG-1 mRNA and protein expression, Bax, Bad, cytosol cytochrome C, Apaf-1, cleaved-caspase-3, and cleaved-caspase-9 protein expression and cytosol cytochrome C concentration, and upregulated TFF1, TFF2 and TFF3 mRNA and protein expression, Bcl-2, Bcl-xl, pro-caspase-3, and pro-caspase-9 protein expression, mitochondrial viability, mitochondrial cytochrome C concentration and Bcl-2/Bax, Bcl-xl/Bad ratios. These findings demonstrated that CSTT protected against IND-induced gastric damage by depressing miR-423-5p expression and modulating the TFF/NAG-1 pathway, which in turn restrained mitochondrion-mediated apoptosis.

Protective effects of camellia oil (Camellia brevistyla) against indomethacin-induced gastrointestinal mucosal damage in vitro and in vivo

Abstract Accumulating evidence reveals that nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, cause oxidative stress and inflammation, which consequently cause gastrointestinal (GI) mucosal damage. Camellia oil, a common edible oil used in Asia, has excellent antioxidative and anti-inflammatory characteristics. Herein, we examined the benefits and protective effects of camellia oil in indomethacin-induced human intestinal Int-407 cells and a mouse model of indomethacin-induced gastric mucosal damage. Camellia oil pretreatment significantly increased cell viability and wound healing and reduced reactive oxygen species production in indomethacin-induced Int-407 cells. In vivo experiments revealed that camellia oil preadministration prevented gastric wound generation by decreasing inflammatory mediators interleukin-6, tumor necrosis factor-α, and cyclooxygenase-2 levels; increasing heme oxygenase-1 antioxidant protein level; and elevating transforming growth factor-β and vascular endothelial growth factor levels in indomethacin-induced BALB/c mice. Thus, camellia oil is a functional dietary oil that prevents oxidative damage and inflammation in NSAID-induced GI mucosal damage.

Pharmacodynamic interaction of 3α-hydroxymasticadienonic acid and diligustilide against indomethacin-induced gastric damage in rats.

The aims of the study were to evaluate the pharmacodynamic interaction between 3α-hydroxymasticadienonic acid and diligustilide (DLG), isolated from the plants Amphiptherygium adstringens and Ligusticum porteri, respectively, using the indomethacin-induced gastric injury model, as well as their individual gastroprotective efficacy in this model. Male Wistar rats were orally administered with 3α-hydroxymasticadienonic acid, DLG or the mixture of 3α-hydroxymasticadienonic acid-DLG (at a fixed-ratio combination of 1:1, 1:3, and 3:1). Thirty minutes later, the gastric damage was induced by a single oral dose of indomethacin (30 mg/kg). Three hours later, the gastric injury (mm2 ) was determined. 3α-hydroxymasticadienonic acid and DLG as individual compounds showed a gastroprotective effect against indomethacin-induced gastric damage (p < .05). The effective dose (ED50 ) values for each compound were 6.96 ± 1.25 mg/kg for 3α-hydroxymasticadienonic acid and 2.63 ± 0.37 mg/kg for DLG. The isobolographic analysis performed showed that the combination exhibited super-additive interaction as the experimental ED50 values (Zexp) were lower than theoretical additive dose values (Zadd; p < .05). Our results identify the super-additive (synergist) interaction between 3α-hydroxymasticadienonic acid and DLG and the gastric safety of both compounds in the indomethacin-induced gastric injury model, suggesting their potential in the future as a strategy to decrease the gastric damage associated to the chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs).

The effects of antioxidant combination on indomethacin-induced gastric mucosal injury in rats

The aim of this study is an investigation the protective effects of vitamin C (Vit C), vitamin E (Vit E), β-carotene, sodium selenate combination in indomethacin-induced gastric mucosal damage in rats. Rats were divided into 6 groups. Group I: Intact animals (control). Group II: Control animals receiving Vit C (100 mg/kg/day), Vit E (100 mg/kg/day), β-carotene (15 mg/kg/day) and sodium selenate (0.2 mg/kg/day) for 3 days. Group III: Animals receiving 25 mg/kg indomethacin. Group IV: Animals receiving Vit C, Vit E, β-carotene and sodium selenate (in same doses) for 3 days 2 h before the administration of indomethacin. Group V: Animals receiving ranitidine (150 mg/kg) for 3 days. Group VI: Animals receiving ranitidine for 3 days 2 h before to the administration of indomethacin (in same dose and time). The administration of indomethacin caused a decrease in the levels of glutathione, mucus, hexosamine and in the activities of glutathione-S-transferase, sodium-potassium ATPase, thromboplastic activity and an increase in the aspartate and alanine amino transferase, alkaline phosphatase, catalase, lactate dehydrogenase, myeloperoxidase activities and sialic acid, lipid peroxidation and protein carbonyl levels. Stomach caspase-8 immun+ cell numbers showed a slight increase while caspase-9 immun+ cell numbers reduced in indomethacin given group compared to control animals. Our results findings suggest that the combination of Vit C, Vit E, β-carotene, sodium selenate and ranitidine has a protective effect on indomethacin-induced gastric mucosal injury of rats.

Protective effects of triple fermented barley extract (FBe) on indomethacin-induced gastric mucosal damage in rats

BackgroundHordeum vulgare L (barley) contains numerous phenolic substances with proven anticancer, antioxidant and gastroprotective activities. Saccharification increases the functionality and bioavailability of these compounds thus can aid in the development of a natural product based medicine. This study aimed to investigate the possible gastroprotective effects of saccharification on the indomethacin (IND)-induced gastric ulcers in rats using Weissella cibaria- and Saccharomyces cerevisiae-triple fermented H. vulgare extract (FBe).MethodsIn total, 60 healthy male 6-week old Sprague-Dawley SD (SPF/VAF Outbred CrljOri:CD1) rats were commercially purchased. The FBe extract (100, 200, and 300 mg kg− 1) was orally administered 30 min before an oral treatment of IND (25 mg kg− 1). Six hours after IND treatment, variations in the histopathology, myeloperoxidase (MPO) activity, gross lesion scores, lipid peroxidation, and antioxidant defense system component (superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH)) levels were measured.ResultsFBe treatment showed significant (p < 0.01 or p < 0.05) and dose-dependent decrease in gastric mucosal damage. In the present study hemorrhagic gross lesions, gastric MPO activity, and histopathological gastric ulcerative lesions were observed in IND-treated rats compared to the IND control rats. In particular, FBe, in a dose-dependent manner, strengthened the antioxidant defense systems, decreased lipid peroxidation and CAT activity by increasing the GSH levels and SOD activity, respectively. The 200 mg kg− 1 dose of FBe was similarly gastroprotective as the 10 mg kg− 1 dose of omeprazole in rats with IND-induced gastric mucosal damage.ConclusionsThe findings of the present study show that an oral administration of FBe had positive gastroprotective effects through strengthening the body antioxidant defense system and anti-inflammatory effects.

Lysophosphatidic acid in medicinal herbs enhances prostaglandin E2 and protects against indomethacin-induced gastric cell damage in vivo and in vitro

Lysophosphatidic acid (LPA) is a bioactive phospholipid that induces diverse biological responses. Recently, we found that LPA ameliorates NSAIDs-induced gastric ulcer in mice. Here, we quantified LPA in 21 medicinal herbs used for treatment of gastrointestinal (GI) disorders. We found that half of them contained LPA at relatively high levels (40–240 μg/g) compared to soybean seed powder (4.6 μg/g), which we previously identified as an LPA-rich food. The LPA in peony (Paeonia lactiflora) root powder is highly concentrated in the lipid fraction that ameliorates indomethacin-induced gastric ulcer in mice. Synthetic 18:1 LPA, peony root LPA and peony root lipid enhanced prostaglandin E2 production in a gastric cancer cell line, MKN74 cells that express LPA2 abundantly. These materials also prevented indomethacin-induced cell death and stimulated the proliferation of MKN74 cells. We found that LPA was present in stomach fluids at 2.4 μM, which is an effective LPA concentration for inducing a cellular response in vitro. These results indicated that LPA is one of the active components of medicinal herbs for the treatment of GI disorder and that orally administered LPA-rich herbs may augment the protective actions of endogenous LPA on gastric mucosa.