Area Of Mucosal Lesions Research Articles

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.

Efficacy of Salvia miltiorrhiza injection combined with steroids in the treatment of oral submucous fibrosis: A meta-analysis of randomized controlled trials.

Background:This study was performed to systematically review the efficacy of Salvia miltiorrhiza injection combined with steroids in the treatment of oral submucous fibrosis.Methods:We searched 9 databases: Web of Science, PubMed, Medline, EBSCO, Embase, The Cochrane Library, WanFang Data, the China National Knowledge Infrastructure (CNKI), and Chinese Scientific Journals Full-text Database (VIP). Randomized controlled trials were collected to study the treatment of oral submucous fibrosis by S miltiorrhiza injection combined with steroids. Each database was searched from inception to November 2018. RevMan 5.3 software was used for the meta-analysis.Results:In total, 13 randomized controlled trials involving 1190 patients were included. The results of the meta-analysis showed that compared with conventional treatment, S miltiorrhiza injection combined with steroids could significantly increase the maximal mouth opening [mean difference (MD), 0.23; 95% confidence interval (CI), 0.16–0.30; P <.0001], decrease the oral mucosal lesion area (MD, −1.35; 95% CI, −2.46 to −0.25; P = .02), improve the subjective symptom burning sensation (MD, −0.77; 95% CI, −1.38 to −0.16; P = .01), and reduce adverse drug reactions (risk ratio, 0.27; 95% CI, 0.14–0.49; P <.0001).Conclusions:The results of this meta-analysis from current evidence showed that compared with conventional treatment, S miltiorrhiza injection combined with steroid could significantly improve the maximal mouth opening and the subjective symptom burning sensation as well as decrease the oral mucosal lesion area without increasing adverse effects.

Targeting MAPKs, NF-κB, and PI3K/AKT pathways by methyl palmitate ameliorates ethanol-induced gastric mucosal injury in rats.

Excessive drinking of alcohol has been frequently associated with gastric injury; however, its underlying molecular mechanisms have been inadequately investigated. Methyl palmitate (MP) has demonstrated marked hepato-, cardio- and pulmonary protective features; however, its effects on ethanol-induced gastric injury have not been studied. The aim of the present study was to evaluate the potential gastroprotective activity of MP against ethanol-evoked gastric mucosal damage in rats and associated molecular mechanisms, for example, mitogen-activated protein kinases (MAPKs), nuclear factor κB (NF-κB), and phosphoinositide 3 kinase/protein kinase B (PI3K/AKT) pathways. The rat stomachs were examined in terms of the inflammatory, oxidative, and apoptotic perturbations. Current data demonstrated that pretreatment with MP attenuated the gross gastric damage, scores of ulcer index, area of mucosal lesions and histopathology outcomes; actions which were similar to the reference antiulcer omeprazole. MP inhibited NF-κB expression, its nuclear translocation, and the expression of its downstream signals, for example, tumor necrosis factor-α and myeloperoxidase besides restoration of interleukin-10 levels. Western blot analysis revealed that MP counteracted the disruption of MAPKs signaling via lowering p-c-Jun N-terminal kinase 1/2 (p-JNK1/2) expression and restoring the phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) levels without affecting p-p38MAPK levels. Additionally, MP improved the antioxidant milieu via diminishing lipid peroxides and enhancing glutathione, glutathione peroxidase, total antioxidant capacity and mucosal nitric oxide. In the context of apoptosis, MP inhibited the cleavage of caspase-3 and poly(ADP-ribose)polymerase (PARP) and Bax protein expression with upregulating B cell lymphoma-2 expression (Bcl-2), thus, promoting gastric cellular survival. This was confirmed by MP activation of the PI3K/AKT pathway manifested by enhanced expression of PI3K p110α and p-AKT. Together, the present findings report the gastroprotective actions of MP mediated via its anti-inflammatory, antioxidant, and antiapoptotic actions. The underlying molecular mechanisms involve, at least partly, the modulation of MAPKs, NF-κB and PI3K/AKT transduction.

Lipopolysaccharide treatment induces adaptive cytoprotection in the portal hypertensive gastric mucosa of rats

Objective: Upper gastrointestinal bleeding in patients with cirrhosis and portal hypertension is a frequent complication that potentially modifies the survival of these patients. This phenomenon may occur due to excessive endotoxin translocation, leading to system debugging liver overload, and systemic endotoxemia, with excessive production of mediators by immune cells. The presence of these inflammatory mediators may increase the susceptibility of gastric mucosa to lesions induced by various damaging agents. As such, this study aimed to determine the resistance of portal hypertensive gastric mucosa to endotoxin and ethanol stimulation. Methods: Portal hypertension was induced in rats by bile duct ligation or portal vein stenosis (PVS) while controls underwent a sham operation. The effect of endotoxin on the gastric mucosa was evaluated by acute or chronic LPS treatment. Ethanol-induced damage was assessed using ex vivo gastric chamber experiments. Gastric blood flow was measured by laser Doppler flowmetry. Results: Acute LPS treatment intensified the ethanol-induced gastric damage in the healthy (control) group in a dose-dependent manner (0.3-3 mg/kg). In contrast, the gastric mucosa of the PVS group presented tolerance after a single dose of LPS (3 mg/kg). Chronic LPS treatment (1 mg/kg) significantly reduced the gastric mucosal lesion area in both the PVS and control groups. Additionally, the cirrhotic animals were found not to survive the minimum dose of LPS. Conclusion: Our results suggest that chronic LPS treatment induces adaptative cytoprotection to ethanol-induced injury in the gastric mucosa of PVS and healthy rats; however, acute LPS treatment increases mortality in cirrhotic rats.

Gastroprotective Effect of NaHS Against Mucosal Lesions Induced by Ischemia–Reperfusion Injury in Rat

Hydrogen sulfide (H(2)S) has been shown to display anti-inflammatory and antioxidant activities. This study was designed to investigate the gastroprotective effect of sodium hydrosulfide (NaHS) on gastric mucosal lesions induced by ischemia-reperfusion (I/R) injury in rats and to determine the possible mechanism involved. Fifty-sex male Wistar rats were randomly assigned into sham, control (I/R injury), propargylglycine (PAG)-, L-cysteine-, and NaHS-treated groups. To induce I/R lesions, the celiac artery was first clamped for 30 min (ischemia phase), followed by removal of the clamp artery to allow reperfusion for 3 h. Treated rats received PAG [50 mg/kg, intravenous (i.v.)] or NaHS (160, 320, or 640 ng/kg, i.v.) 5 min before reperfusion. The effect of L-cysteine pretreatment was also investigated. Plasma levels of cytokines and cortisol were measured by an enzyme-linked immunosorbent assay. The gastric tissue samples were collected to quantify the mRNA expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and transforming growth factor (TGF-β) by quantitative real-time PCR. The total area of gastric lesions significantly decreased following the administration of NaHS and L-cysteine. The highest area of mucosal lesions was observed in PAG-treated rats. The mRNA expression and plasma levels of IL-1β and TNF-α were significantly decreased in L-cysteine- and NaHS-treated rats in a dose-dependent manner. Slightly increased levels of TGF-β were observed in these test groups, but the difference was not statistically significant compared with the other groups. The plasma level of cortisol was also not affected by NaHS treatment. Our findings indicate that a possible mechanism for the gastroprotective effect of H(2)S could be through the decreased mRNA expression and plasma release of proinflammatory cytokines.

Gastroprotective potential of frutalin, a d-galactose binding lectin, against ethanol-induced gastric lesions

The present study was designed to verify whether frutalin (FTL) affords gastroprotection against the ethanol-induced gastric damage and to examine the underlying mechanism(s). Gastric damage was induced by intragastric administration of 0.2ml of ethanol (96%). Mice in groups were pretreated with FTL (0.25, 0.5 and 1mg/kg; i.p.), cimetidine (100mg/kg; p.o.), or vehicle (0.9% of NaCl, 10mL/kg; p.o.), 30min before ethanol administration. They were sacrificed 30min later, the stomachs excised, and the mucosal lesion area (mm2) measured by planimetry. Gastroprotection was assessed in relation to inhibition of gastric lesion area. To study the gastroprotective mechanism(s), its relations to capsaicin-sensitive fibers, endogenous prostaglandins, nitric oxide, sulphydryls, ATP-sensitive potassium channels, adrenoceptors, opioid receptors and calcium channels were analyzed. Treatments effects on ethanol-associated oxidative stress markers GSH and MDA were measured in gastric tissue. FTL afforded a dose-unrelated gastroprotection against the ethanol damage. However, it failed to prevent the ethanol-induced changes in the levels of GSH and MDA. It was observed that the gastroprotection by FTL was greatly reduced in animals pretreated with capsazepine, indomethacin, L-NAME or glibenclamide. Considering the results, it is suggested that the FTL could probably be a good therapeutic agent for the development of new medicine for the treatment of gastric ulcer.

Protective effect of anacardic acids from cashew (Anacardium occidentale) on ethanol-induced gastric damage in mice

Cashew nut-shell liquid and the contained anacardic acids (AAs) have been shown to possess antioxidant, lipoxygenase inhibitory, anti-Helicobacter pylori and antitumor properties. Despite these known effects, hitherto there were no published reports on their likely gastroprotective effects. The present study was designed to verify whether AAs afford gastroprotection against the ethanol-induced gastric damage and to examine the underlying mechanism(s). Gastric damage was induced by intragastric administration of 0.2mL of ethanol (96%). Mice in groups were pretreated orally with AAs (10, 30 and 100mg/kg), misoprostol (50 microg/kg), or vehicle (2% Tween 80 in saline, 10mL/kg), 45min before ethanol administration. They were sacrificed 30min later, the stomachs excised, and the mucosal lesion area (mm(2)) measured by planimetry. Gastroprotection was assessed in relation to inhibition of gastric lesion area. To study the gastroprotective mechanism(s), its relations to capsaicin-sensitive fibers, endogenous prostaglandins, nitric oxide and ATP-sensitive potassium channels were analysed. Treatments effects on ethanol-associated oxidative stress markers GSH, MDA, catalase, SOD, and total nitrate/nitrite levels as an index of NO were measured in gastric tissue. Besides, the effects of AAs on gastric secretory volume and total acidity were analysed in 4-h pylorus-ligated rat. AAs afforded a dose-related gastroprotection against the ethanol damage and further prevented the ethanol-induced changes in the levels of GSH, MDA, catalase, SOD and nitrate/nitrite. However, they failed to modify the gastric secretion or the total acidity. It was observed that the gastroprotection by AAs was greatly reduced in animals pretreated with capsazepine, indomethacin, l-NAME or glibenclamide. These results suggest that AAs afford gastroprotection principally through an antioxidant mechanism. Other complementary mechanisms include the activation of capsaicin-sensitive gastric afferents, stimulation of endogenous prostaglandins and nitric oxide, and opening of K(+)(ATP) channels. These combined effects are likely to be accompanied by an increase in gastric microcirculation.

Role of dietary fibres, intestinal hypermotility and leukotrienes in the pathogenesis of NSAID-induced small intestinal ulcers in cats

Background:Recent advances in endoscopy have revealed that non-steroidal anti-inflammatory drugs (NSAIDs) often cause ulcers in the human small intestine. However, the mechanism of intestinal ulcer formation is still unclear.Aims:The role...

Effect of Passive Cigarette Smoking on Colonic α7-Nicotinic Acetylcholine Receptors in TNBS-Induced Colitis in Rats

Background and Aims: Cigarette smoking affects colonic inflammation, but the exact mechanism by which it does so is unclear. The aim of this study was to investigate the underlying mechanism by examining the effect of cigarette smoking on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. Method: Experimental colitis was induced by administrating TNBS enema in Sprague-Dawley rats. The effect of cigarette smoking was assessed by measuring the colonic edema, mucosal lesion area, histopathological score, mucosal myeloperoxidase (MPO) activity and tumor necrosis factor-α (TNF-α). The expression of α7-nicotinic acetylcholine receptor (α7nAChR) was examined after cigarette smoking to identify whether the α7nAChR is involved in inflammation. Results: TNBS induced severe colitis as evidenced by increased colonic edema, mucosal lesion area, histopathological score, MPO activity, and TNF-α level. Inflammation was aggravated by cigarette smoke exposure. Colonic tissue expressed α7nAChR (0.41 ± 0.11), and TNBS up-regulated the receptor expression (0.46 ± 0.11), but the difference was not significant (p > 0.05). Cigarette smoking with 2 and 4% respectively significantly increased the expression of α7nAChR (0.55 ± 0.05 and 0.64 ± 0.08) (p < 0.05). Conclusions: The up-regulated expression of α7nAChR after exposure to cigarette smoking indicates that α7nAChR in colonic tissue may be involved in cigarette smoking damage in TNBS-induced colitis in rats.

Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG

The gastric mucosa is frequently exposed to different exogenous and endogenous ulcerative agents. Alcoholism is one of the risk factors for the development of mucosal damage in the stomach. This study aimed to assess if a probiotic strain Lactobacillus rhamnosus GG (LGG) is capable of protecting the gastric mucosa from acute damage induced by intragastric administration of ethanol. Pre-treatment of rats with LGG at 109 cfu/ml twice daily for three consecutive days markedly reduced ethanol-induced mucosal lesion area by 45%. LGG pre-treatment also significantly increased the basal mucosal prostaglandin E2 (PGE2) level. In addition, LGG attenuated the suppressive actions of ethanol on mucus-secreting layer and transmucosal resistance and reduced cellular apoptosis in the gastric mucosa. It is suggested that the protective action of LGG on ethanol-induced gastric mucosal lesions is likely attributed to the up-regulation of PGE2, which could stimulate the mucus secretion and increase the transmucosal resistance in the gastric mucosa. All these would protect mucosal cells from apoptosis in the stomach.

Heparin and low-molecular-weight heparin (enoxaparin) significantly ameliorate experimental colitis in rats.

The anticoagulants, unfractionated heparin and low-molecular-weight heparin, demonstrated anti-inflammatory effects in animal models and in humans. Because of its dual effects, high-dose heparin was proposed as a therapeutic modality for ulcerative colitis. We investigated whether a low dose of low-molecular-weight heparin-enoxaparin (Clexane, Rhône-Poulenc Rorer, France)-ameliorates the inflammatory response in two models of experimental colitis. Colitis was induced in rats by intrarectal administration of dinitrobenzene sulphonic acid. Enoxaparin (40, 80 and 200 microg/kg) or unfractionated heparin (100, 200 and 400 U/kg) were administered subcutaneously immediately after the induction of damage. Enoxaparin, 80 microg/kg, was also administered after induction of colitis by intrarectal administration of iodoacetamide. Rats were sacrificed 1, 3 or 7 days after induction of injury. Colonic damage was assessed macroscopically and histologically. Mucosal prostaglandin E2 generation, myeloperoxidase and nitric oxide synthase activities and tumour necrosis factor-alpha levels in blood were determined. Enoxaparin and heparin significantly ameliorated the severity of dinitrobenzene sulphonic acid- and iodoacetamide-induced colitis as demonstrated by a decrease in mucosal lesion area, colonic weight and mucosal myeloperoxidase and nitric oxide synthase activities. The dose-response curve had a bell-shaped configuration: enoxaparin, 80 microg/kg, and unfractionated heparin, 200 U/kg, were the optimal doses. Low-dose enoxaparin and unfractionated heparin ameliorate the severity of experimental colitis. This effect is related to their anti-inflammatory rather than anticoagulant properties.

Zinc sulphate solution enema decreases inflammation in experimental colitis in rats.

It has been reported that zinc sulphate contributes an anti-inflammatory action in many animal models; however, the impact of zinc in colitis remains unclear. The aim of the present study was to examine the role of zinc sulphate in experimental colitis. Colitis was induced by 2,4,6-trinitrobenzenesulphonic acid (TNB) in rats. Beginning at the first day of TNB colitis, the rats were treated with a zinc sulphate enema once daily for 6 days. The rats were examined 8 days later. The TNB induced severe colitis as evidenced by increased mucosal lesion area, mucosal myeloperoxidase (MPO) activity and prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels. Six days after the application of the zinc sulphate enema, the mucosal lesion area, MPO activity, PGE2 and LTB4 levels all decreased significantly. Mucosal superoxide dismutase activity remained unchanged after zinc treatments. Our data suggest that zinc sulphate enemas have an anti-inflammatory action on experimental colitis.

Oxidative stress in gastric mucosal injury: role of platelet-activating factor-activated granulocytes.

Temporal and spatial changes due to oxidative stress in the rat gastric mucosa were visualized and quantified during the process of mucosal hemorrhagic change. The fluorescence associated with dichlorofluorescein (DCF), a hydroperoxide-sensitive fluorochrome, increased 30 min after repeated electrical stimuli to the gastric artery. The increase in the fluorescence was enhanced in the area between two adjacent collecting venules. The content of platelet-activating factor (PAF), the activity of myeloperoxidase (MPO) in the gastric mucosa, the area of mucosal lesions, and the luminol-dependent chemiluminescence activity in zymosan-treated blood samples, obtained from the gastric vein, were measured and found to increase significantly 30 min after the stimuli. The intravenous injection of CV-6209, a PAF antagonist, 5 min prior to the stimuli significantly inhibited the DCF activation, the increases in PAF level and MPO activity, the mucosal hemorrhagic change, and the elevation in chemiluminescence activity. In addition, continuous infusion of superoxide dismutase also inhibited all these changes, except for chemiluminescence activity. These results suggest that oxygen radicals derived from PAF-activated granulocytes induce oxidative stress, and that oxidative changes are actually implicated in the pathogenesis of gastric mucosal injury.

A stable nitroxide radical effectively decreases mucosal damage in experimental colitis.

TEMPOL, a cyclic nitroxide stable radical blocks biological damage by breaking chain reactions through termination reaction with free radicals, and by inhibiting the catalytic effect of transition metals. This study tested its protective effect on two models of experimental colitis as free radicals play an important part in their pathogenesis. TEMPOL was given intragastrically immediately after induction of colitis with acetic acid or trinitrobenzene sulphonic acid (TNB) and mucosal damage was assessed one, three, or seven days later. Cellular partition of TEMPOL was determined by electron paramagnetic resonance spectroscopy. In vitro experiments showed that TEMPOL immediately penetrates colonic mucosa and, following its intragastric administration, it persists in both gastric and colonic mucosa for several hours. Intragastric administration of TEMPOL, 0.5 g/kg/bw, immediately after intracaecal administration of 5% acetic acid significantly decreased mucosal lesion area, myeloperoxidase activity, and leukotriene B4 and C4 generation when assessed 24 hours after damage induction. Intragastric administration of TEMPOL, 0.5 g/kg/bw, immediately after intracolonic administration of 30 mg TNB in 0.25 ml 50% ethanol, and once daily thereafter, significantly decreased mucosal lesion area assessed after one, three, and seven days, having no effect on LTC4 generation and affecting colonic weight, myeloperoxidase activity, and LTB4 generation only sporadically. In conclusion, TNB and acetic acid induced colitis can be pharmacologically manipulated by TEMPOL. TEMPOL may be beneficial in the treatment or prevention of inflammatory bowel disease.

A role for calcitonin gene-related peptide in protection against gastric ulceration.

The goal of this investigation was to determine the role of calcitonin gene-related peptide (CGRP) in gastric mucosal resistance to ulceration. CGRP is a 37-amino acid peptide found in the peripheral ends of afferent gastric neurons. CGRP is known to inhibit acid secretion, stimulate mucosal blood flow, and stimulate release of somatostatin. The release of CGRP in response to intragastric and intra-arterial administration of capsaicin in the isolated, vascularly perfused rat stomach was measured by radioimmunoassay. The molecular forms of CGRP released were analyzed by gel filtration chromatography. The effect of intravenous CGRP or intragastric capsaicin on gastric ulceration induced by 100 mmol/L HCl and indomethacin was studied in intact and endogenous CGRP-depleted rats. Intra-arterial capsaicin (concentration range, 10(-7) to 10(-5) mol/L) stimulated a prompt and sustained release of immunoreactive CGRP, of which 84% coeluted with rat 1-37 CGRP I by gel filtration. Intragastric capsaicin (range, 10(-5) to 10(-4) mol/L) failed to release CGRP into the vascular perfusate. In intact rats, intragastric capsaicin (10(-6) mol/L) or intravenous CGRP I (10 micrograms/kg/hr) reduced the number and area of mucosal lesions caused by HCl and indomethacin compared with the findings in control rats. Rats depleted of endogenous CGRP were more susceptible to gastric ulceration than were normal rats. Intragastric capsaicin failed to protect the mucosa of CGRP-depleted rats, whereas exogenous intravenous CGRP was effective. These data support the hypothesis that CGRP released from gastric enteric neurons mediates gastric mucosal resistance to ulceration by noxious agents.