Stress-induced Gastric Ulcers Research Articles

Overexpression of HSP27 accelerates stress-induced gastric ulcer healing via the CXCL12/CXCR4 axis.

Chronic stress often triggers gastrointestinal complications, including gastric injury and ulcers. Understanding the role of heat shock protein 27 (HSP27) in stress-induced gastric ulcers could unveil novel therapeutic targets. Here, we established a stress-induced gastric ulcer rat model using water immersion restraint stress and administered adenovirus-packaged HSP27 overexpression vector. Gastric ulcer severity was scored, and mucosal changes were assessed. Gastric epithelial and endothelial cells were treated with lipopolysaccharide and transfected with HSP27 overexpression vectors to evaluate cell viability, migration and angiogenesis. Expression levels of HSP27, C-X-C motif chemokine ligand 12 (CXCL12) and C-X-C motif chemokine receptor 4 (CXCR4) were measured in tissues and cells. HSP27 expression was initially low during stress-induced gastric ulceration but increased during ulcer healing. HSP27 overexpression accelerated ulcer healing in rats, promoting gastric epithelial cell proliferation and migration and gastric endothelial cell angiogenesis through the CXCL12/CXCR4 axis. Inhibitor IT1t reversed the effects of HSP27 overexpression on cell proliferation, migration and angiogenesis. In summary, HSP27 overexpression facilitated ulcer healing, which was partially mediated by the CXCL12/CXCR4 axis.

A comprehensive review on phytochemicals as potential therapeutic agents for stress-induced gastric ulcer

AbstractGastric ulcers are the most common chronic gastrointestinal tract disorders, marked by an inflamed break of the mucus membrane covering the alimentary tract. According to recent research, stress-induced ulcers are widespread in our society. A stress ulcer is a mucosal defect that may become complicated due to upper gastrointestinal tract bleeding. The underlying cause of this condition is pH. Physiological stress leads to severe sickness by triggering the excessive secretion of peptic juices or gastric acid. There is a never-ending quest for safe and affordable medication for this disorder. Nature offers many medicinal plants that can be used to treat a wide range of human ailments. Due to their relatively harmless and comparatively free of harmful effects, health-promoting features, pharmacological practices, and affordability to common people to regulate various diseases, medicinal plants, and herbal preparations are gaining a lot of interest in scientific communities these days. Many studies have recently been performed to classify extracts and their constituents that may have a therapeutic effect on peptic ulcers. Therefore, this review aims to address the molecular mechanisms and pharmacological effects of various phytochemicals related to stress-induced gastric ulcers. Combining phytochemical constituents with modern drugs and treatment methods can lead to the development of therapeutic drugs for gastric ulcers. Gastric ulcers and other related diseases may be treated permanently with this approach.

Banxia Xiexin decoction promotes gastric lymphatic pumping by regulating lymphatic smooth muscle cell contraction and energy metabolism in a stress-induced gastric ulceration rat model

Ethnopharmacological relevanceThe traditional Chinese medicine (TCM) formula Banxia Xiexin decoction (BXD) has definite therapeutic effect in treating stress-induced gastric ulceration (SIGU) and many other gastrointestinal diseases, but its effect on gastric lymphatic pumping (GLP) remains unclear. Aim of the studyElucidating the role of GLP in SIGU and BXD treatment, and exploring the molecular mechanisms of GLP regulation. Materials and methodsIn vivo GLP imaging were performed on SIGU rat model, and the lymphatic dynamic parameters were evaluated. Gastric antrum tissues and serum were collected for macroscopic, histopathological and ulcerative parameters analysis. Gastric lymphatic vessel (GLV) tissues were collected for RNA-Seq assays. Differentially expressed genes (DEGs) were screened from RNA-Seq result and submitted for transcriptomic analysis. Key DEGs and their derivative proteins were measured by qRT-PCR and WB. ResultsGLP was significantly suppressed in SIGU rats. BXD could recover GLP, ameliorate stomach lymphostasis, and alleviate the ulcerative damage. Transcriptome analysis of GLV showed the top up-DEGs were concentrated in smooth muscle contraction signaling pathway, while the top the down-DEGs were concentrated in energy metabolism pathways especially fatty acid degradation pathway, which indicated BXD can promote lymphatic smooth muscle contraction, regulate energy metabolism, and reduce fatty acid degradation. The most possible target of these mechanisms was the lymphatic smooth muscle cells (LSMCs) which drove the GLP. This speculation was further validated by the qRT-PCR and WB assessments for the level of key genes and proteins. ConclusionsBy activating the smooth muscle contraction signaling pathway, restoring energy supply, modulating energy metabolism program and reducing fatty acid degradation, BXD effectively recovered GLP, mitigated the accumulation of inflammatory cytokines and metabolic wastes in the stomach, which importantly contributes to its efficacy in treating SIGU.

Systematic Exploration of the Potential Material Basis and Molecular Mechanism of the Mongolian Medicine Shudage-4 in Attenuating Stress-Induced Gastric Ulcer in Rat.

Shudage-4, an ancient and well-known formula in traditional Mongolian medicine comprising four different types of traditional Chinese medicine, is widely used in the treatment of gastric ulcers. However, the potential material basis and molecular mechanism of Shudage-4 in attenuating stress-induced gastric ulcers remain unclear. This study aimed to first explore the potential material basis and molecular mechanism of Shudage-4 in attenuating gastric ulcers in rats. The chemical constituents and transitional components in the blood of Shudage-4 were identified by ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS). The rat gastric ulcer model was induced by water immersion restraint stress (WIRS). The ulcer damage to gastric tissue was measured at the gross anatomical level and pathological level by hematoxylin-eosin (HE) staining of gastric tissue. RNA sequencing of gastric tissue and plasma metabolomics were performed to analyze the mechanism of Shudage-4 against gastric ulcers. A Pearson correlation analysis was performed to explore the association between serum metabolites and gene expression of gastric tissue. A total of 30 chemical constituents were identified in Shudage-4 by UPLC-TOF-MS. Among 30 constituents, 13 transitional components in the blood were considered as the potential material basis. Shudage-4 treatment had a significant effect on WIRS-induced gastric ulcers in rats. HE staining of gastric tissue illustrated that WIRS-induced ulcer damage was suppressed by Shudage-4 treatment. RNA sequencing of gastric tissue showed that 282 reversed expression genes in gastric tissue were related to Shudage-4 treatment, and gene set enrichment analysis revealed that Shudage-4 treatment significantly inhibited gene set expression related to reactive oxygen species (ROS), which was also validated by detecting rat gastric tissue MDA, GSH, SOD, GSH-Px, and CAT activities. The plasma metabolomic data demonstrated that 23 significantly differential metabolites were closely associated with the Shudage-4 treatment. The further multiomics joint analysis found that significantly upregulated 5 plasma metabolites in Shudage-4-treated rats compared to model rats were negatively correlated with gene set expression related to ROS in gastric tissue. Shudage-4 alleviated WIRS-induced gastric ulcers by inhibiting ROS generation, which was achieved by regulating plasma metabolites level.

Role of 5-HT1A Receptor on Fluvoxamine induced Gastrointestinal Mucosa Protection and Healing in Animal with Stress-Induced Gastric Ulcer

One factor that could contribute to the developing of gastric ulcer is stress. Fluvoxamine, an SSRI antidepressant showed protective effects to ulcers when administered before stress induction. In opposite, administration of fluvoxamine after stress induction delayed the mucosa healing. This study aimed to investigate the effects of pre-treatment and post-treatment of buspirone a 5-HT1A receptor partial agonist in the inhibition of gastric mucosal protection and healing by fluvoxamine in animals with stress-induced gastric ulcers. This study used ddY, male mice, weighed 25-30grams, which divided into two groups, pre-treatment and post-treatment groups. Each group consisted of subgroups that were administered low doses of buspirone (0.1mg/Kg and 0.3mg/Kg) and high doses of buspirone (10.0mg/Kg and 30.0mg/Kg). In the pre-treatment group, buspirone was administered intraperitoneally at 60 minutes before and continued with oral fluvoxamine 100mg/Kg administration at 30 minutes before stress induction. In the post-treatment group, buspirone was administered intraperitoneally followed fluvoxamine orally 30 minutes after stress induction done. The stress model used is water immersion restrain stress for 6 hours. In the pre-treatment group, the combination of high dose, but not low dose buspirone significantly inhibit the protection effects of fluvoxamine on stress-induced gastric ulcers. In addition, in the post-treatment group, the combination of low dose buspirone and fluvoxamine strengthen the delays of mucosal healing by fluvoxamine in mice with stress-induced gastric ulcers. Fluvoxamine protects and heals gastric mucosa from stress-induced gastric ulcer through the activation of 5HT1A receptor.

Piper sarmentosum Roxb. methanolic extract prevents stress-induced gastric ulcer by modulating oxidative stress and inflammation.

This study investigated the gastroprotective effect of Piper sarmentosum (PS) on stress-induced gastric ulcers in rats by measuring its effect on oxidative stress, gastric mucosal nitric oxide (NO), and inflammatory biomarkers. Twenty-eight male Wistar rats were randomly divided into four groups; two control groups (non-stress and stress) and two treated groups supplemented with either methanolic PS extract (500mg/kg body weight) or omeprazole (OMZ; 20mg/kg) orally. After 28days of treatment, the stress control, PS, and OMZ groups were subjected to water-immersion restrain stress (WIRS) for 3.5h. Gastric tissue malondialdehyde (MDA), NO, superoxide dismutase (SOD), inducible NO synthase (iNOS), SOD mRNA, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels were measured. WIRS significantly increased gastric MDA, NO, and pro-inflammatory cytokine levels compared to the non-stressed control group. PS and omeprazole supplementation significantly reduced WIRS-exposure-induced gastric ulcers and MDA, iNOS, and IL-1β levels. However, only PS reduced NO, TNF-α, and IL-6 levels, which were upregulated in this ulcer model. In conclusion, the gastroprotection afforded by PS is possibly mediated by gastric mucosal NO normalization through reduced iNOS expression and attenuation of inflammatory cytokines. PS showed a greater protective effect than omeprazole in reducing gastric lesions and NO, TNF-α, and IL-6 levels, and iNOS expression.

Curative Effects of Triphala Extract against Swim Stress-Induced Gastric Ulcers via Reduced Ulcer Index, Strengthened Gastric Mucosa and Improved Redox State in Rats

Curative Effects of Triphala Extract against Swim Stress-Induced Gastric Ulcers via Reduced Ulcer Index, Strengthened Gastric Mucosa and Improved Redox State in Rats

CHARACTERISTICS OF CYTOPROTECTIVE EFFECT ON THE GASTRIC MUCOSA OF CRYOPRESERVED PLACENTA EXTRACT UNDER WATER-IMMOBILIZATION STRESS

Various stressors are currently considered to play a significant role among the etiological factors for development of peptic ulcer disease. Along with psycho-emotional stressing experiences, the causes of formation of stress ulcers include major surgical interventions, thermal or mechanical injuries, severe blood loss, progressive syndrome of endogenous intoxication and more. Among patients in intensive care units, the incidence of stress ulcers is 5.0%, and in 30.0-50.0% of cases stress ulcers are complicated by bleeding and perforation.
 Aim. The research aims at characterizing the gastrocytoprotective effect of cryopreserved placenta extract (CEP) on the model of water-immobilization stress in rats according to macroscopic data and the results of biochemical study of homogenates of the gastric mucosa (GM).
 Materials and Methods. In vivo experimental studies were performed on 28 nonlinear laboratory male rats weighing 200-220 g. Stress-induced gastric ulcer was simulated under water-immobilization stress (WIS) in rats. WIS simulation according to the method of Takagi K.Y. et al. The activity of NO synthases (NOS) in GM was determined spectrophotometrically by the amount of oxidized NADPH+H+.
 Results and Discussion. The use of CEP, as well as esomeprazole, led to a weakening of GM ulcers. This was indicated by a statistically significant (p<0.05) decrease in ulcer index (UI) relative to the indicators of control rats by 9.8 and 3.3 times, respectively. At the same time, this indicator was three times lower on the background of preventive use of CEP than in rats treated with esomeprazole, respectively, antiulcer activity (AUA) was 96.4% and 69.2%. The study of the activity of constitutive (cNOS) and inducible (iNOS) isoforms of NOS showed that at the pathobiochemical level against the background of stress-induced ulcerogenesis in the tissues of the central nervous system there is a statistically significant (p<0.001) increase in iNOS activity in 5.2 times was 0.89±0.01 NADPH2/min´g protein. According to the degree of modulation of the activity of both total NOS and its individual isoforms, the study showed that preventive five-day administration of esomeprazole is inferior to the effectiveness of CEP. Thus, the activity of total NOS in rats administered esomeprazole was statistically significantly (p<0.001) decreased by only 17.1%, while the activity of this enzyme decreased (p<0.001) by 35.8% due to the use of CEP.
 Conclusions. Prophylactic five-day administration of CEP modulated the activity of the NOS system in the central nervous system, which in a macroscopic study appeared statistically significant (p<0.05) reduction in UI relative to rats in the control group by 9.8 times. Thus, NOS activity statistically significantly (p<0.001) decreased by 35.8%, and iNOS activity statistically significantly (p<0.001) decreased by 58.4% relative to the control animals. CEP under the prophylactic regimen showed more pronounced anti-ulcer activity than esomeprazole, which was 96.4% and 69.2%, respectively.

Modulation of lipid peroxidation and energy metabolism in the gastric mucosa as a mechanism ofantiulcer activity of placental cryoextract in the healing of stress-induced ulcers

Background. Peptic ulcer disease has a leading place in the overall structure of digestive diseases: its prevalence is 6.00–10.0% of the population in developed countries, and mortality ranges from 6 to 9.7 per 100 thousand population. An important etiological factor of this pathology is the neuropsychological background, primarily stress, which under repeated exposure becomes the initiating factor of physiological imbalance between the elements of aggression and protection of the gastric mucosa. The purpose was to establish the mechanisms of the protective activity of placental cryoextract based on the biochemical indicators of lipid peroxidation and antioxidant protection in the gastric mucosa on a model of stress-induced erosive-ulcerative damage. Materials and methods. Studies were performed on 28 nonlinear laboratory male rats weighing 200–220g. Stress-induced gastric ulcer was modeled under water-immobilization stress in rats according to the K.Y. Takagi etal. In the gastric mucosa, the content of reactants with thiobarbituric acid was determined spectrophotometrically by the method of T. Asakawa etal., catalase activity— spectrophotometrically by the method of M.A.Korolyuk etal., the content of reduced glutathione— spectrophotometrically by the method of E.D. Beutler etal., the level of adenyl nucleotides was determined using chromatographic method. Energy charge was calculated by D.E. Atkinson equation. Results.The prophylactic five-day use of placental cryoextract led to a decrease in the severity of stress-induced lipid peroxidation and energy imbalance in the gastric mucosa. Thus, it was found that rats who received placental cryoextract had a statistically significant (p<0.001) increase in adenosine triphosphate content by 73.3%, an increase in adenosine diphosphate (p<0.001) by 37.3% and a decrease in adenosine monophosphate (p<0.001) by 47.6% that led to an increase in energy charge (p<0.001) by 35.1% compared to rats exposed to water-immobilization stress without correction (control group). It was shown that the use of placental cryoextract led to a statistically significant (p<0.001) increase in the antioxidant-prooxidant index by 3.1 times versus control group, which was (26.60±0.96) and (8.60±0.43), respectively. Conclusions. Prophylactic five-day administration of placental cryoextract leads to the restoration of balance in the system of adenyl nucleotides and, accordingly, to a statistically significant (p<0.001) increase in the energy charge by 35.1% compared to the control animals. Inhibition of stress-induced hyperactivation of lipid peroxidation in the gastric mucosa is one of the mechanisms of its antiulcer activity.

Peripheral administration of Neuropeptide-W protects against stress-induced gastric injury in rats

AimsNeuropeptide W (NPW) participates in the regulation of neuroendocrine response to stress, but the possible protective effects of NPW against stress-induced gastric ulcers have not yet been evaluated. The purpose of the present study was to investigate whether peripherally administered NPW could have gastroprotective effects in water-immersion restraint stress (WIRS)-induced gastric injury. Main methodsSprague-Dawley rats were subjected to WIRS for 6 h, and treated with NPW (0.1, 0.3, 1 and 5 μg/kg) or saline at 30 min before WIRS application. Under anesthesia, capsaicin (1 %) was applied perivagally for degeneration of vagal afferent fibers (VAD) at two weeks before WIRS protocol. Blood, gastric and brain tissues were obtained for biochemical, molecular and histological assessments. Key findingsNPW treatment given immediately before WIRS application attenuated stress-induced gastric oxidant damage along with an increase in gastric blood flow, while similar gastroprotective effects were observed in NPW-treated rats with denervated vagal afferents. NPW prevented elevations in serum IL-6 and TNF-α levels, and increased cycloxygenase-1 mRNA, but suppressed cycloxygenase-2 mRNA levels. In addition, WIRS-induced downregulation of NPW expression in the brain tissue was reversed in NPW-treated rats having less severe ulcers, suggesting that cerebral NPW production could be critical in the central regulation of stress-induced ulcerogenesis. SignificanceOur results demonstrate for the first time that the peripheral administration of NPW offers an anti-ulcer activity in stress-induced gastric ulcer by regulating gastric blood flow, suppressing oxidant damage and inflammation via the modulation of COX-induced gastroprotection and without the contribution of vagal afferent fibers.

The Protective Effect of Polysaccharide SAFP from Sarcodon aspratus on Water Immersion and Restraint Stress-Induced Gastric Ulcer and Modulatory Effects on Gut Microbiota Dysbiosis.

Sarcodon aspratus is a popular edible fungus for its tasty flavour and can be used as a dietary supplement for its functional substances. This study was conducted to evaluate the potential health benefits of Sarcodon aspratus polysaccharides (SAFP) on water immersion and restraint stress (WIRS)-induced gastric ulcer in rats. The results indicated that SAFP could decrease myeloperoxidase (MPO) activity and plasma corticosterone levels, as well as enhance Prostaglandin E2 (PGE2) and Nitrate/nitrite (NOx) concentration in rats. Furthermore, SAFP significantly attenuated the stress damage, inflammation, pathological changes and gastric mucosal lesion in rats. Moreover, high-throughput pyrosequencing of 16S rRNA suggested that SAFP modulated the dysbiosis of gut microbiota by enhancing the relative abundance of probiotics, decreasing WIRS-triggered bacteria proliferation. In summary, these results provided the evidence that SAFP exerted a beneficial effect on a WIRS-induced gastric ulcer via blocking the TLR4 signaling pathway and activating the Nrf2 signaling pathway. Notably, SAFP could modulate the WIRS-induced dysbiosis of gut microbiota. Thus, SAFP might be explored as a natural gastric mucosal protective agent in the prevention of gastric ulcers and other related diseases in the food and pharmaceutical industries.

Graphene quantum dots alleviate ROS-mediated gastric damage

SummaryThe gastrointestinal (GI) tract is one of the major sites for reactive oxygen species generation (ROS). Physiological ROS, lower than the threshold concentration, is beneficial for human physiology to preserve gut functional integrity. However, ROS generated in large quantities in presence of external stimuli overwhelms the cellular antioxidant defense mechanism and results in oxidative damage and associated physiological disorder. Graphene quantum dots (GQDs) are a class of carbon-based nanomaterials that have attracted tremendous attention not only for their tunable optical properties but also for their broad-spectrum antioxidant properties. In this report we have shown that GQDs are highly efficient in scavenging ROS and suppressing stress-induced gastric ulcers by targeting the MMP-9 pathway and reducing the inflammatory burden by suppressing excessive oxidative stress by inducing high caspase activity, overproduction of Bax, and downregulation of BCL2.

The dual gastro- and neuroprotective effects of curcumin loaded chitosan nanoparticles against cold restraint stress in rats

Stress is a condition affecting different body systems. Curcumin (CUR) is a natural compound that has various pharmacological benefits. However, its poor oral bioavailability limits its therapeutic value. This study aimed to formulating curcumin loaded chitosan nanoparticles (CS.CUR.NPs) and investigate its gastroprotective and neuroprotective effects in rats subjected to cold restraint stress (CRS), in reference to conventional oral CUR preparation, and explore its underlying mechanism. Treated groups received either CUR or CS.CUR.NPs (100 mg∕kg) orally for 14 days before exposure to CRS. CRS elicited marked behavioral changes and gastric ulcer accompanied by histopathological abnormalities of the brain and stomach along with elevation of pain score. CUR and CS.CUR.NPs improved stress-induced gastric ulcer, cognitive performance, and pain sensation. Mechanistically, CRS disrupts oxidative and inflammatory status of the brain as manifested by high malondialdehyde and IL-6 and low total antioxidant capacity and IL-10, along with high C-reactive protein level. CRS decreased nuclear factor erythroid 2-related factor2 (Nrf2) and increased nuclear factor-kappa B (NF-κB) expressions. Furthermore, brain levels of unphosphorylated signal transducer and activator of transcription3 (U-STAT3) and glial fibrillary acidic protein (GFAP) were upregulated with stress. CUR and CS.CUR.NPs provided beneficial effects against harmful consequences resulting from stress with superior beneficial effects reported with CS.CUR.NPs. In conclusion, these findings shed light on the neuroprotective effect of CUR and CS.CUR.NPs against stress-induced neurobehavioral and neurochemical deficits and protection against stress-associated gastric ulcer. Moreover, we explored a potential crosslink between neuroinflammation, U-STAT3, NF-κB, and GFAP in brain dysfunction resulted from CRS.

Therapeutic Effects of Vitamin E in Gastric Stress Ulcers and Obesity in Rats

Stress – related disturbances are classified among the health problems that have global interest, especially which are related to gastrointestinal system. The consequent oxidative stress is confirmed to be responsible for the development of gastric mucosal ulcers and necrosis. That is accompanied with the release of different inflammatory mediators. On the other hand, the ratio of obesity is gradually increasing in the world. It impairs the quality of life because of its associated serious complications. Vitamin E is a fat-soluble, free radicals scavenger antioxidant. It has anti-inflammatory and cell membrane-stabilizing properties. Besides, it has anti – obesity effects. The present study highlights the potential therapeutic effects of vitamin E in the treatment of stress-induced gastric ulcers in rats. Stomach injury was induced in fasted rats by cold- restraint stress (CRS) method. Vitamin E was administered orally at a dose of 100 mg/kg for 7 consecutive days. Rats were sacrificed on the 8th day. Assessment of the stomach injury was by studying body weight changes, macroscopic examinations, histological study, and determination of oxidative stress markers (MDA stomach content and SOD enzyme activity). Vitamin E administration alleviated the stomach injury degree, and caused a remarkable body weight decrease, with a statistical significance in comparison with the stressed group. Vitamin exerted good effects in reducing body weight, and healing of stress-induced gastric ulcers in rats.

Increasing Aspartoacylase in the Central Amygdala: The Common Mechanism of Gastroprotective Effects of Monoamine-Based Antidepressants Against Stress.

Monoamine-based antidepressants can prophylactically protect against stress-induced gastric ulcers. Although the central nucleus of amygdala (CeA) has been shown to modulate the severity of stress ulcers, little is known about the molecular mechanisms underlying the gastroprotective effect of this kind of drugs. Here, we first used proton magnetic resonance spectroscopy, a non-invasive tool, to explore the change of neurometabolites of the CeA of rats pretreated with the duloxetine of selective serotonin-norepinephrine reuptake inhibitors during 6 h of water-immersion restraint stress (WIRS). Duloxetine decreased N-acetyl-aspartate/creatine ratio (NAA/creatine) in CeA after WIRS, which was paralleled by the amelioration of gastric lesions. Meanwhile, the gastric ulcer index was negatively correlated with reduced NAA/creatine. Furthermore, the intra-CeA infusion of NAA aggravated WIRS-induced gastric mucosa damage, which suggested the crucial role of reduced NAA. Western blotting was performed to identify the specific enzymes responsible for the change of the contents of NAA at 0.5 h/3 h/6 h after WIRS, considering the preventative gastric protection of duloxetine. The NAA-catabolizing enzyme aspartoacylase (ASPA) was the only enzyme downregulated by 0.5 h WIRS and upregulated by duloxetine. Moreover, overexpressing ASPA in CeA alleviated stress ulcers. Additionally, all of the other three monoamine-based antidepressants, the fluoxetine of selective serotonin reuptake inhibitors, the amitriptyline of tricyclic agents, and the moclobemide of MAOs, increased ASPA expression in CeA. Together, these results indicate that increasing ASPA to hydrolyze NAA in CeA is a common mechanism of gastroprotective effects against stress exerted by monoamine-based antidepressants, and ASPA is a shared target more than monoamine regulation for this kind of drugs.

Omeprazole prevents stress induced gastric ulcer by direct inhibition of MMP-2/TIMP-3 interactions

The healing of damaged tissues in gastric tract starts with the extracellular matrix (ECM) remodeling by the action of matrix metalloproteinases (MMPs). Particularly, MMP-2 (gelatinase-A) maintains ECM structure and function by degrading type IV collagen, the major component of basement membranes and by clearing denatured collagen. The proteolytic activities of MMPs are critically balanced by endogenous tissue inhibitors of metalloproteinases (TIMPs) and disruption of this balance results in several diseases. The well-known drug omeprazole is a proton pump inhibitor used for curing gastric ulcer. However, the action of omeprazole in ECM remodeling on gastroprotection has never been explored. Herein, using rat model of gastric ulcer, we report that restraint cold stress caused increase apoptosis to surface epithelia of gastric tissues along with TIMP-3 upregulation and inhibition of MMP-2 activity thereon. In contrast, omeprazole treatment suppressed TIMP-3 while increasing MMP-2 activity and thereby, restoring MMP-2/TIMP-3 balance. Additionally, nanomolar binding constant (Kd = 318 nM) of omeprazole with purified MMP-2 indicates a direct effect of omeprazole in restoring MMP-2 activity. Further in silico simulations revealed a plausible mechanism of action of omeprazole for TIMP-3 deactivation. Altogether, omeprazole restores MMP-2 activity and reduces apoptosis while preventing acute stress-induced gastric ulcer that occurs via suppression of nuclear factor kappa B (NF-κB) activity and peroxisome proliferator-activated receptor gamma activity (PPAR-γ). This represents an unprecedented correlation between physical docking of drug molecule to a protease and the severity of organ injury and provides a novel therapeutic approach to prevent stress induced tissue damage.

THE EFFECT OF PLACENTAL CRYOEXTRACT ON THE STATE OF PROTEIN-LIPID METABOLISM IN THE GASTRIC MUCOSA IN EXPERIMENTAL STRESS-INDUCED ULCERS

Introduction. Peptic ulcer is one of the most prevalent diseases of the gastrointestinal tract. Stress factor is considered to have the highest impact on the development of ulcers, as it is present in almost all cases of onset and exacerbation of this disease. Acute stress ulcers occur with severe injuries, acute diseases of various organs, shock, a sharp drop in blood pressure, oxygen deficiency of body tissues, liver, kidney and others. Given the above facts, in the correction of stress-induced lesions of the gastric mucosa (GM) therapeutically, the target should consider not only reducing the aggression factors of gastric juice, but also the normalization of changes in protein and carbohydrate metabolism in GM. In this aspect, our attention was drawn to the domestic biotechnological preparation of placental cryoextract (CEP), which has a range of valuable biological effects. The aim is to study the effect of cryopreserved placenta extract on the state of protein-lipid metabolism in the gastric mucosa in a model of water-immobilization stress in rats. Materials and methods of research. The studies were performed on 28 nonlinear laboratory male rats weighing 200–220 g. Stress-induced gastric ulcer was modeled under water-immobilization stress (WIS) in rats according to the method of Takagi et al. To obtain the homogenate, the GM was perfused with cold (+ 4°C) buffer solution and homogenized at 3000 rpm (teflon/glass). The content of oxidatively modificated proteins (OMP) in GM was determined by Dubinina spectrophotometric method. The content of total lipids in the GM was determined spectrophotometrically by color reaction with sulfophosphovaniline reagent. Phospholipids (PL) were fractionated by the method of Svetashev and Vaskovsky. Research results. Evaluation of changes in protein metabolism in GM showed that the level of total protein in rats, which were preventively administered CEP before WIS, was almost comparable with that of intact rats, i.e., 50.1 ± 1.7 μg/mg tissue and 51.1 ± 1.3 μg/mg of tissue, respectively, which indicated the elimination of disorders of protein homeostasis with the introduction of the studied cryoextract. Studies of changes in total lipids and PL showed that the content of PL of animals treated with CEP was 26.9 ± 0.9%, which was not significantly different from that of intact animals (30.5 ± 0.9%) and, at the same time, it was by 7.3% higher (p < 0.001) as compared with animals who were administered esomeprazole. Conclusions. Prophylactic five-day administration of CEP to WIS leads to normalization of all evaluated indices, in particular, to increase of the total protein level by 29.0% (p <0.01), decrease of oxidatively modified proteins level by 20.6% (p <0.01), and the 2.3-fold increase (p <0.001) of the level of phospholipids in the total lipids pool.

Gastroprotective effects of hydrogen sulfide, carbon monoxide and nitric oxide on an experimental ulcer model in rats

Background/Aim: Gastric mucosal injury induced by several agents such as ethanol, stress or nonsteroidal anti-inflammatory drugs (NSAIDs) is a common severe disorder. Hydrogen sulfide (H2S), carbon monoxide (CO) and nitric oxide (NO) are gaseous autacoids that are endogenously produced in mammalian tissues. Recently, several studies confirmed that H2S, CO and NO play a role in gastroprotection. Our work aimed to evaluate and compared the gastroprotective effects of H2S, CO and NO on ethanol-, indomethacin- and stress-induced rat ulcer models. Methods: The effects of NaHS (5 mg/kg), CORM-2 (5 mg/kg) and L-arginine (100 mg/kg) were investigated on gastric ulcer models induced by ethanol (1 ml 96% i.g.), stress (cold+immobility) and indomethacin (40 mg/kg i.g.). The ulcer index, gastric mucus secretion, free and total acidity, and levels of TNF-α, PGE2, MDA GSH, COX-1, COX-2 were measured. Results: NaHS and CORM-2 decreased the increased TNF-α and MDA levels in ethanol-induced ulcer. L-arginine reduced mucin secretion, TNF-α and GSH levels in stress-induced gastric ulcer. Conclusion: The present study showed that H2S and CO may have gastroprotective activity against ethanol-induced ulcers and NO may be gastroprotective against stress-induced ulcers.

Gastroprotective effect of fluvoxamine and ondansetron on stress-induced gastric ulcers in mice.

The association between stress and gastric ulcers has been well reported. This study is divided into two parts: the first part of this study is consisted of analyzing the effect of fluvoxamine administration by intracerebroventricular (ICV) and intraperitoneal (IP) injections on stress-induced gastric ulcers. The second part investigates the effect of ondansetron in influencing the protection of the gastric mucous by giving fluvoxamine to the mice before being induced with stress. Water immersion restraint stress (WIRS) was used to induce stress. Fluvoxamine 50 and 100mg/kg by IP injection, fluvoxamine 9.3µg, and 18.6µg by ICV injection 30min before the induction of stress. Meanwhile, single drug and in combination administered to the mice, ondansetron 3mg/kg was given by IP at 60min, and fluvoxamine 50, 100mg/kg orally at 30min before stress induction. The obtained results show fluvoxamine 50 and 100mg/kg by IP, and fluvoxamine 18.6µg by ICV had significantly reduced ulcer index with p<0.005, p<0.001, and p<0.005 while fluvoxamine 9.3µg showed the insignificant result. Fluvoxamine 50mg/kg, fluvoxamine 100mg/kg, and ondansetron 3mg/kg monotherapy have a significant reduction in ulcers with p<0.005, p<0.001, and p<0.05, while the combination drugs showed an insignificant reduction in ulcers. Fluvoxamine with different administration routes and ondansetron monotherapy before stress reduce the occurrence of gastric ulcers, while the combination drugs did not increase the protective effect of the gastric mucosa.

Sodium R-lipoate and enzymatically-modified isoquercitrin suppressed IgE-independent anaphylactic reactions and stress-induced gastric ulceration in mice

Anaphylaxis is a life-threatening allergic reaction, for which the worldwide prevalence is rapidly increasing. The currently used synthetic antiallergic drugs have a high tendency to cause adverse effects, like gastric ulcers, in long-term use. Therefore, a great deal of attention has been given to develop new safer and more effective antiallergic agents from natural compounds that are chemically/enzymatically-modified. Here, we evaluated/compared the efficacy of two different doses (50 and 100 mg/kg body weight “b.w”, given orally) of sodium R-lipoate (NaRLA) and enzymatically-modified isoquercitrin (EMIQ) in alleviating both local/systemic non-immunological anaphylactic reactions and stress-induced gastric ulceration in mice, in comparison with sulfasalazine (SSZ) as a reference drug. The results indicated that the pre-treatment of animals with NaRLA or EMIQ (especially at 100 mg/kg b.w) completely succeeded, as SSZ, in alleviating the hind paw edema induced by either histamine or compound 48/80 (Cpd 48/80). Furthermore, NaRLA and EMIQ prevented the mast cell degranulation and anaphylactic shock caused by Cpd 48/80 (in a dose-dependent manner) and reduced significantly (P < 0.001) the histamine release from the mouse peritoneal mast cells, like SSZ. Moreover, their use was associated with alleviating both gastric histopathological and biochemical alterations in the water-restraint stress (WRS) mice model towards the control values. They also decreased the percentage of degranulated mesenteric mast cells in the WRS mice model. In conclusion, our findings provide possibility that both NaRLA and EMIQ may serve as an effective therapeutic agents for mast cells-dependent anaphylactic reactions without risks of inducing gastric ulcers.