Search

Background: Hp infection in Mongolian gerbils is an experimental model of gastric carcinogenesis. It remains unknown whether anti-Hp triple therapy influences pathological and functional aspects accompanying Hpinduced cancer cascade especially gastric acid secretion, gastric blood flow (GBF) and gastrin-somatostatin link. Aim: To compared the effects of intragastric (i.g.) inoculation of Mongolian gerbils with Hp strain (cagA+ vacA+) to those induced by vehicle in gerbils with or without gastric fistula at 2, 4, 12, 30 weeks upon gastric Hp inoculation. Methods: The effect of triple therapy (omeprazole, amoxicillin and tinidazol) was determined for 5 consecutive days starting from 24 h post infection. Histology, the viable Hp and density of Hp colonization were evaluated and the gastric blood flow (GBF), gastrin plasma and gastric luminal somatostatin were determined. Hp was detected by histology, culture and urease test. Results: Initial basal gastric acid (45 umol/h) in non-infected gerbils was reduced by 55% after Hp inoculation and persisted during time tested in Hp-infected but not in those with triple therapy. First lesions were seen 4 weeks after Hp inoculation and consisted of chronic gastritis with inflammatory cell infiltration, multiple gastric lymphoid follicle and typical adenomatous hyperplasia. In Hp-infected gerbils plasma gastrin concentration increased with significant fall of gastric somatostatin level and GBF. These effects were abolished in gerbils treated with anti-Hp triple therapy. Conclusions: 1) Hp-infection in Mongolian gerbils in early stages of adenocarcinoma formation results in the development of typical functional and pathological changes such as suppression of gastric secretion and impairment of both, gastric mucosal GBF and gastrin-somatostatin link and 2) this deleterious influence of Hp on gastric morphology and function could be reversed by anti-Hp triple therapy that prevent carcinogenesis in these species. [ABSTRACT FROM AUTHOR]

Background and Aims: LPS is the major virulence factor in Hp-infected stomach. Whether gastric mucosa can adapt to prolonged treatment with this endotoxin or water extract of Hp (WE-Hp) containing LPS and whether such adaptation can influence aspirin (ASA) induced gastric damage have been little studied. Methods: We compared the effect of single and 5-day repeated intragastric (i.g.) administration of Hp-LPS or WE-Hp with those induced by LPS isolated from Campylobacter jejuni, Yersinia enterocolitica and Bacteroides fragilis on gastric secretion in rats (series A) and acute gastric lesions induced at day 5 by ASA (series B). Hp-LPS and WE-Hp were prepared from antral biopsy of Hp-infected patients. Gastric blood flows (GBF) and lesions area were measured. Plasma leptin, gastrin, IL-1beta and TNFalpha were determined using RIA or ELISA. Gastric mucosa leptin mRNA was analyzed by RT-PCR. Results: Hp-LPS (0.01-5 mg/kg i.g.) or WE-Hp (1 ml i.g.) inhibited the gastric acid secretion (series A) and produced gastric damage which disappeared after 5 daily exposures. It was accompanied by GBF, plasma gastrin and leptin levels increase (series B). Intestinal LPS (1 mg/kg i.g.) inhibited gastric secretion and produced negligible damage also disappeared at day 5. ASA alone caused gastric lesions, decreased GBF and raised the plasma IL-1beta and TNFalpha levels 2-3 fold. The ASA damage was attenuated in rats treated 5 times with Hp-LPS and WE-Hp or intestinal LPS. These effects were accompanied by GBF increase, leptin mRNA upregulation, plasma immunoreactive leptin and gastrin concentration increase, IL-1beta and TNFalpha levels decrease. Conclusions: 1) Gastric mucosa may adapt to intestinal endotoxins similarly to that observed in Hp-LPS and WE-Hp treated mucosa and 2) adaptation to Hp cytotoxins enhances mucosal resistance to subsequent ASA damage possibly by inhibition of acid secretion, gastric microcirculation enhancement, proinflammatory cytokines attenuation and... [ABSTRACT FROM AUTHOR]

Presents a corrigendum related to gastrointestinal pH profiles among patients with inflammatory bowel disease. Statistical analysis relative to patients remission; Data on Crohn disease; Role of oxygen metabolites in aspirin-induced gastric damage.

Gastric ulcers affect approx. 10% of population. Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA) predispose to or impair the physiologically complex healing of pre-existing ulcers. Since H 2 S is an endogenous cytoprotective molecule, we hypothesized that new H 2 S-releasing ASA-derivative (ATB-340) could overcome pathological impact of NSAIDs on GI regeneration.Clinically translational gastric ulcers were induced in Wistar rats using state-of-the-art microsurgical model employing serosal application of acetic acid. This was followed by 9 days long i.g. daily treatment with vehicle, ATB-340 (6-24 mg/kg) or equimolar ASA doses (4-14 mg/kg). Ulcer area was assessed macro- and microscopically. Prostaglandin (PG)E2  levels, indicating pharmacological activity of NSAIDs and 8-hydroxyguanozine content, reflecting nucleic acids oxidation in serum/gastric mucosa, were determined by ELISA. Qualitative and/or quantitative pathway-specific alterations at the ulcer margin were evaluated using real-time PCR and mass spectrometry-based proteomics.ASA, unlike ATB-340, dose-dependently delayed/impaired gastric tissue recovery, deregulating 310 proteins at the ulcer margin, including Ras signalling, wound healing or apoptosis regulators. ATB-340 maintained NSAIDs-specific cyclooxygenase-inhibiting capacity on systemic and GI level but in time-dependent manner. High dose of ATB-340 (24 mg/kg daily), but not ASA, decreased nucleic acids oxidation and upregulated anti-oxidative/anti-inflammatory heme oxygenase-1, 24-dehydrocholesterol reductase or suppressor of cytokine signalling (SOCS3) at the ulcer margin.Thus, ASA impairs the physiological healing of pre-existing gastric ulcers, inducing the extensive molecularly functional and proteomic alterations at the wound margin. H 2 S-releasing ATB-340 maintains the target activity of NSAIDs with limited impact on gastric PGE2 signalling and physiological GI regeneration, enhancing anti-inflammatory and anti-oxidative response, and providing the pharmacological advantage., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Recently discovered irisin, a member of the myokines family, is a potential mediator of exercise-induced energy metabolism and a factor promoting browning of the white adipose tissue. Recent evidence indicates that this myokine, released from contracting muscles, can mediate the beneficial effects of exercise on health. Irisin may be a potential therapeutic agent against obesity and has been shown to play an important role in the protection of various cells, tissues, and organs due to its anti-inflammatory, antioxidative, and anti-cancer properties. Our aim was to review the recent experimental and clinical studies on irisin and its expression, release into the bloodstream, tissue targets, and potential contribution to the protective effects of exercise in the gastrointestinal tract. Particular emphasis was placed on inflammatory bowel disease, intestinal ischemia/reperfusion injury, periodontitis, and other digestive tract disorders, including carcinogenesis. Overall, irisin holds significant potential as a novel target molecule, offering a safe and therapeutic approach to treating various gastrointestinal diseases., Competing Interests: The authors declare no conflicts of interest.

Intestinal alkaline phosphatase (IAP) is an enzyme that plays a protective role in the gut. This study investigated the effect of IAP treatment on experimental colitis in mice subjected to forced exercise on a high-fat diet. C57BL/6 mice with TNBS colitis were fed a high-fat diet and subjected to forced treadmill exercise with or without IAP treatment. Disease activity, oxidative stress, inflammatory cytokines, and gut microbiota were assessed. Forced exercise exacerbated colitis in obese mice, as evidenced by increased disease activity index (DAI), oxidative stress markers, and proinflammatory adipokines and cytokines. IAP treatment significantly reduced these effects and promoted the expression of barrier proteins in the colonic mucosa. Additionally, IAP treatment altered the gut microbiota composition, favoring beneficial Verrucomicrobiota and reducing pathogenic Clostridia and Odoribacter. IAP treatment ameliorates the worsening effect of forced exercise on murine colitis by attenuating oxidative stress, downregulating proinflammatory biomarkers, and modulating the gut microbiota. IAP warrants further investigation as a potential therapeutic strategy for ulcerative colitis.

The discovery of Helicobacter pylori (Hp) infection of gastric mucosa leading to active chronic gastritis, gastroduodenal ulcers, and MALT lymphoma laid the groundwork for understanding of the general relationship between chronic infection, inflammation, and cancer. Nevertheless, this sequence of events is still far from full understanding with new players and mediators being constantly identified. Originally, the Hp virulence factors affecting mainly gastric epithelium were proposed to contribute considerably to gastric inflammation, ulceration, and cancer. Furthermore, it has been shown that Hp possesses the ability to penetrate the mucus layer and directly interact with stroma components including fibroblasts and myofibroblasts. These cells, which are the source of biophysical and biochemical signals providing the proper balance between cell proliferation and differentiation within gastric epithelial stem cell compartment, when exposed to Hp, can convert into cancer-associated fibroblast (CAF) phenotype. The crosstalk between fibroblasts and myofibroblasts with gastric epithelial cells including stem/progenitor cell niche involves several pathways mediated by non-coding RNAs, Wnt, BMP, TGF-β, and Notch signaling ligands. The current review concentrates on the consequences of Hp-induced increase in gastric fibroblast and myofibroblast number, and their activation towards CAFs with the emphasis to the altered communication between mesenchymal and epithelial cell compartment, which may lead to inflammation, epithelial stem cell overproliferation, disturbed differentiation, and gradual gastric cancer development. Thus, Hp-activated fibroblasts may constitute the target for anti-cancer treatment and, importantly, for the pharmacotherapies diminishing their activation particularly at the early stages of Hp infection., (© 2023. The Author(s).)

The gut mucosal barrier plays a key role in the physiology of gastrointestinal (GI) tract, preventing under homeostatic conditions, the epithelial cells of the gastric mucosa from hydrochloric acid and intestinal mucosa from alkaline secretion, food toxins and pathogenic microbiota. Previous studies have documented that blockade of both isoforms of cyclooxygenase (COX): constitutive (COX-1) and inducible (COX-2), as well NO synthase in the stomach exacerbated the gastric damage induced by various ulcerogens, however, such as effects of non-selective and selective inhibition of COX-1, COX-2 and NOS enzymes on colonic damage have been little studied. The supplementation of NO by intragastric (i.g.) treatment with NO-releasing compound NO-aspirin (NO-ASA) or substrate for NO synthase L-arginine ameliorated the damage of upper GI-tract, but whether similar effect can be observed in colonic mucosa associated with the experimental colitis, and if above mentioned compounds can be effective in aggravation or protection of experimental colitis remains less recognized. In this study rats with experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzosulphonic acid (TNBS) were daily treated for 7 days with: 1) vehicle (i.g.), 2) ASA 40 mg/kg (i.g.), 3) rofecoxib 10 mg/kg (i.g.), 4) resveratrol 10 mg/kg (i.g.), 5) NO-ASA 40 mg/kg (i.g.), 6) L-arginine 200 mg/kg (i.g.) with or without of L-NNA 20 mg/kg (i.p.). The macroscopic and microscopic area of colonic damage was determined planimetrically, the colonic blood flow (CBF) was assessed by Laser flowmetry, and the oxidative stress biomarkers malondialdehyde and 4-hydroxynonenal (MDA+4-HNE), the antioxidative factors superoxide dismutase (SOD) and glutathione (GSH), as well as proinflammatory cytokines in the colonic mucosa (tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β)) were measured. We have documented that administration of TNBS produced gross and microscopic colonic damage and significantly decreased CBF (p<0.05). Treatment with ASA significantly increased the area of colonic damage (p<0.05), an effect accompanied by a significant decrease in the CBF, the significant increment of MDA+4-HNE, and the attenuation of the antioxidative properties in colonic mucosa, documented by a significant decrease of SOD activity and GSH concentration, and elevation of the colonic tissue levels of TNF-α and IL-1β comparing to control Veh-treated TNBS rats. Administration of rofecoxib or resveratrol also significantly increased the colonic damage and significantly decreased the CBF, causing an increase in MDA+4-HNE and mucosal content of TNF-α and IL-1α and a significant decrease of the SOD activity and GSH content (p<0.05), however, these changes were significantly less pronounced as compared with ASA. On the contrary, the treatment with NO-ASA, or L-arginine, significantly diminished the area of colonic lesions, the MDA+4-HNE concentration, attenuated the TNF-α and IL-1β levels, while increasing the CBF, SOD activity and GSH content (p<0.05). The concomitant treatment of L-NNA with rofecoxib or resveratrol reversed an increase in area of colonic damage and accompanying changes in CBF, colonic mucosa TNF-α and IL-1β levels, the MDA+4-HNE concentration, and SOD activity and GSH content comparing to those observed in TNBS rats treated with these COX-inhibitors alone (p<0.05). In contrast, co-treatment with L-NNA and NO-ASA or L-arginine failed to significantly affect the decrease of colonic lesions accompanied by the rise in CBF, the attenuation of MDA+4-HNE concentration, TNF-α and IL-1β levels, SOD activity and GSH content exerted by NO-ASA- or L-arginine treatment of the respective control TNBS-rats without L-NNA administration. These observations suggest that 1) the increase of NO availability either from NO-releasing donors such as NO-ASA or NO precursors such as L-arginine, can inhibit the inflammatory and microvasculature alterations, as well as increase in lipid peroxidation due to the enhanced efficacy of these compounds to increase the antioxidative properties of colonic mucosa, 2) unlike ASA which exacerbated the severity of colitis, the treatment with rofecoxib, the specific 'safer' COX-2 inhibitor or resveratrol, the polyphenolic compound known to act as the dual COX-1 and COX-2 inhibitor, can attenuate the colonic damage during course of TNBS colitis possibly via anti-inflammatory and antioxidative properties, and 3) the blockade of endogenous NO activity by L-NNA which also exacerbated the severity of mucosal damage in colitis, can abolish the sparing effect of rofecoxib and resveratrol indicating the NO bioavailability plays an important role in enhanced efficacy of both specific and dual COX inhibitors to ameliorate the experimental colitis.

Hydrogen sulfide (H 2 S) emerged recently as an anti-oxidative signaling molecule that contributes to gastrointestinal (GI) mucosal defense and repair. Indomethacin belongs to the class of non-steroidal anti-inflammatory drugs (NSAIDs) and is used as an effective intervention in the treatment of gout- or osteoarthritis-related inflammation. However, its clinical use is strongly limited since indomethacin inhibits gastric mucosal prostaglandin (PG) biosynthesis, predisposing to or even inducing ulcerogenesis. The H 2 S moiety was shown to decrease the GI toxicity of some NSAIDs. However, the GI safety and anti-oxidative effect of a novel H 2 S-releasing indomethacin derivative (ATB-344) remain unexplored. Thus, we aimed here to compare the impact of ATB-344 and classic indomethacin on gastric mucosal integrity and their ability to counteract the development of oxidative gastric mucosal injuries. Wistar rats were pretreated intragastrically (i.g.) with vehicle, ATB-344 (7-28 mg/kg i.g.), or indomethacin (5-20 mg/kg i.g.). Next, animals were exposed to microsurgical gastric ischemia-reperfusion (I/R). Gastric damage was assessed micro- and macroscopically. The volatile H 2 S level was assessed in the gastric mucosa using the modified methylene blue method. Serum and gastric mucosal PGE 2 and 8-hydroxyguanozine (8-OHG) concentrations were evaluated by ELISA. Molecular alterations for gastric mucosal barrier-specific targets such as cyclooxygenase-1 (COX)-1, COX-2, heme oxygenase-1 (HMOX)-1, HMOX-2, superoxide dismutase-1 (SOD)-1, SOD-2, hypoxia inducible factor (HIF)-1α, xanthine oxidase (XDH), suppressor of cytokine signaling 3 (SOCS3), CCAAT enhancer binding protein (C/EBP), annexin A1 (ANXA1), interleukin 1 beta (IL-1β), interleukin 1 receptor type I (IL-1R1), interleukin 1 receptor type II (IL-1R2), inducible nitric oxide synthase (iNOS), tumor necrosis factor receptor 2 (TNFR2), or H 2 S-producing enzymes, cystathionine γ-lyase (CTH), cystathionine β-synthase (CBS), or 3-mercaptopyruvate sulfur transferase (MPST), were assessed at the mRNA level by real-time PCR. ATB-344 (7 mg/kg i.g.) reduced the area of gastric I/R injuries in contrast to an equimolar dose of indomethacin. ATB-344 increased gastric H 2 S production, did not affect gastric mucosal PGE 2 content, prevented RNA oxidation, and maintained or enhanced the expression of oxidation-sensitive HMOX-1 and SOD-2 in line with decreased IL-1β and XDH. We conclude that due to the H 2 S-releasing ability, i.g., treatment with ATB-344 not only exerts dose-dependent GI safety but even enhances gastric mucosal barrier capacity to counteract acute oxidative injury development when applied at a low dose of 7 mg/kg, in contrast to classic indomethacin. ATB-344 (7 mg/kg) inhibited COX activity on a systemic level but did not affect cytoprotective PGE 2 content in the gastric mucosa and, as a result, evoked gastroprotection against oxidative damage.

Acute pancreatitis (AP) is the most common gastrointestinal disease leading to hospitalizations and unexpected deaths. The development of AP leads to damage of the pancreatic microcirculation with a cascade of subsequent events resulting, among others, in coagulopathy. Previous research showed that anticoagulants can be important therapeutic agents. Heparin and acenocoumarol can alleviate the course of AP, as well as accelerate healing and post-inflammatory regeneration of the pancreas. The aim of this study was to determine whether warfarin, a drug with more stable effects than acenocoumarol, affects the healing and regeneration of the pancreas in the cerulein-induced AP. AP was evoked in Wistar male rats by intraperitoneal administration of cerulein. The first dose of warfarin (45, 90 or 180 μg/kg) was administered 24 hours after the first dose of cerulein and the doses of warfarin were repeated once a day in subsequent 10 days. The severity of AP was assessed immediately after the last dose of cerulein, as well as at days 1, 2, 3, 5, and 10 after AP induction. Treatment with warfarin dose-dependently increased international normalized ratio (INR) and attenuated the severity of pancreatitis in histological examination and accelerated pancreatic recovery. These effects were accompanied with a faster reduction in the AP-evoked increase in serum activity of amylase and lipase, the serum concentration of pro-inflammatory interleukin-1β, and the plasma level of D-Dimer. In addition, treatment with warfarin decreased pancreatic weight (an index of pancreatic edema) and improved pancreatic blood flow in rats with AP. The therapeutic effect was particularly pronounced after the administration of warfarin at a dose of 90 μg/kg. We conclude that treatment with warfarin accelerated regeneration of the pancreas and recovery in the course of cerulein-induced mild-edematous acute pancreatitis.

The aim of the study was to check the possibility of reusing aggregate from recycled concrete waste and rubber granules from car tires as partial substitution of natural aggregate. The main objective was to investigate the effects of recycled waste aggregate modified with polymer fibers on the compressive and flexural strength, modulus of elasticity and permeability of pervious concrete. Fibers with a multifilament structure and length of 54 mm were deliberately used to strengthen the joints among grains (max size 31.5 mm). Eight batches of designed mixes were used in the production of pervious concrete at fixed water/binder ratio of 0.34 with cement content of 350 kg/m 3 . Results showed that the use of recycled concrete aggregate (8/31.5 mm) with replacement ratio of 50% (by weight of aggregate) improved the mechanical properties of pervious concrete in all analyzed cases. Whereas the replacement of 10% rubber waste aggregate (2/5 mm) by volume of aggregate reduced the compressive strength by a maximum of 11.4%. Addition of 2 kg/m 3 of polymer fibers proved the strengthening effect of concrete structure, enhancing the compressive and tensile strengths by a maximum of 23.4% and 25.0%, respectively. The obtained test results demonstrate the possibility of using the recycled waste aggregates in decarbonization process of pervious concrete production, but further laboratory and field performance tests are needed.

Melatonin (MEL) is produced and secreted by the pineal gland as well as the small intestine, liver, retina, lymphocytes, and melanocytes in the skin in both experimental animals as well as in humans. While pineal and retinas MEL is closely related to the light/dark cycle, the production of MEL by other so called extrapineal tissues is independent of such circadian rhythm. Among the primary mechanisms of action of MEL in humans, the most important are interaction of MEL with specific receptors (M1, M2, M3) and the MEL 'scavenging' activity against the formation of free oxygen metabolites as a result of MEL's ability to transfer free electrons and stimulation of the expression of redox reaction enzymes. In addition, MEL binds to intracellular proteins such as calmodulin, thereby affecting the course of cell cycle, and it has been shown to activate of nuclear receptors belonging to the retinoid orphan receptors/retinoid Z receptors (ROR/RZR) subfamily. MEL exerts regulatory effects on the master clock regulating diurnal rhythms. This updated review presents current view on the synthesis and metabolism of MEL and the growing body of experimental evidence transferable to the practical medicine supporting a pleiotropic molecule beneficial effects on the health including protection against various organ abnormalities, including internal organs such as the liver. Although the beneficial effects of MEL in various types of liver damage have been well documented in experimental studies, there are relatively few studies on liver dysfunction in humans. Considering the worldwide obesity pandemic often associated with the occurrence of steatohepatitis and cirrhosis, the beneficial effects of MEL in liver pathology should be proven in randomized trials involving patients presenting with hepatic disorders.

Obesity may be treated by bariatric procedures and is related to enterohormone release modulation. Nevertheless, a majority of commonly used surgical procedures have a significant impact on vagus nerve function by breaking the connections with its gastric branches. In the case of an intragastric balloon (BAL), this interaction is unclear. However, BAL-induced weight reduction is not long-lasting. Interestingly, this method has not been used in combination with vagotomy (VAG). Thus, we evaluated, for the first time, the short- and long-term effects of combined BAL and VAG using the animal-based translational model and compared these effects with sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). Wistar rats were fed a high-calorie diet for 8 weeks to induce obesity before SG, RYGB, BAL + / - VAG. Animals' weight and eating behaviors were monitored weekly. After 90 days, serum samples were collected to evaluate postprandial and fasting GLP-1, GIP, PYY, ghrelin, glucagon, insulin, leptin, and pancreatic polypeptide concentrations by fluorescent assay. VAG, SG, RYGB, and BAL + VAG significantly reduced body weight 30 and 90 days after surgery. BAL alone induced temporal weight reduction observed after 30 days, reversed after 90 days. Calories intake was reduced at the first half of the observation period in all groups. Fluid intake was reduced in all groups except SG and BAL. Enterohormone profile for BAL + VAG was comparable to SG and RYGB but not BAL. VAG and BAL + VAG but not BAL alone maintain weight reduction, alimentary intake changes, and enterohormone release after long-term observation. VAG may improve the effectiveness of bariatric procedures for obesity treatment in clinical practice., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Both obesity and esophageal adenocarcinoma (EAC) rates have increased sharply in the United States and Western Europe in recent years. EAC is a classic example of obesity-related cancer where the risk of EAC increases with increasing body mass index. Pathologically altered visceral fat in obesity appears to play a key role in this process. Visceral obesity may promote EAC by directly affecting gastroesophageal reflux disease and Barrett's esophagus (BE), as well as a less reflux-dependent effect, including the release of pro-inflammatory adipokines and insulin resistance. Deregulation of adipokine production, such as the shift to an increased amount of leptin relative to "protective" adiponectin, has been implicated in the pathogenesis of BE and EAC. This review discusses not only the epidemiology and pathophysiology of obesity in BE and EAC, but also molecular alterations at the level of mRNA and proteins associated with these esophageal pathologies and the potential role of adipokines and myokines in these disorders. Particular attention is given to discussing the possible crosstalk of adipokines and myokines during exercise. It is concluded that lifestyle interventions to increase regular physical activity could be helpful as a promising strategy for preventing the development of BE and EAC.

Despite of the improvement in gastric cancer (GC) therapies patients still suffer from cancer recurrence and metastasis. Recently, the high ratio of these events combined with increased chemoresistance has been related to the asymptomatic Helicobacter pylori ( Hp ) infections. The limited efficiency of GC treatment strategies is also increasingly attributed to the activity of tumor stroma with the key role of cancer-associated fibroblasts (CAFs). In order to investigate the influence of Hp infection within stromal gastric tissue on cancer initiation and progression, we have exposed normal gastric epithelial cells to long-term influence of Hp -activated gastric fibroblast secretome. We have referred obtained results to this secretome influence on cancer cell lines. The invasive properties of cells were checked by time-lapse video microscopy and basement membrane assays. The expression of invasion-related factors was checked by RT-PCR, Western Blot, immunofluorescence and Elisa. Hp -activated gastric fibroblast secretome induced EMT type 3-related shifts of RGM1 cell phenotype; in particular it augmented their motility, cytoskeletal plasticity and invasiveness. These effects were accompanied by Snail1/Twist activation, the up-regulation of cytokeratin19/FAP/TNC/Integrin-β1 and MMPs, and by the induction of cMet high /pEGFR high phenotype. Mechanistic studies suggest that this microevolution next to TGFβ relies also on c-Met/EGFR signaling interplay and engages HGF-Integrin-Ras-dependent Twist activation leading to MMP and TNC upregulation with subsequent positive auto- and paracrine feedback loops intensifying this process. Similar shifts were detected in cancer cells exposed to this secretome. Collectively, we show that the secretome of Hp -infected fibroblasts induces reprogramming/microevolution of epithelial and cancer cells towards type 3 EMT-related invasive phenotype in a manner reciprocally reliant next to TGFβ on cMet/Integrin-β1/p-EGFR-dependent axis. Apparently, the phenotypical plasticity of Hp -activated fibroblast reprogrammed gastric epithelial cells determines their susceptibility to the pro-invasive signaling, which results in re-organization of gastric niches and provides the cues for GC promotion/progression., Competing Interests: None., (AJCR Copyright © 2022.)

Inflammatory bowel diseases (IBD) are commonly considered as Crohn's disease and ulcerative colitis, but the possibility that the alterations in gut microbiota and oxidative stress may affect the course of experimental colitis in obese physically exercising mice treated with the intestinal alkaline phosphatase (IAP) has been little elucidated. Mice fed a high-fat-diet (HFD) or normal diet (ND) for 14 weeks were randomly assigned to exercise on spinning wheels (SW) for 7 weeks and treated with IAP followed by intrarectal administration of TNBS. The disease activity index (DAI), grip muscle strength test, oxidative stress biomarkers (MDA, SOD, GSH), DNA damage (8-OHdG), the plasma levels of cytokines IL-2, IL-6, IL-10, IL-12p70, IL-17a, TNF-α, MCP-1 and leptin were assessed, and the stool composition of the intestinal microbiota was determined by next generation sequencing (NGS). The TNBS-induced colitis was worsened in obese sedentary mice as manifested by severe colonic damage, an increase in DAI, oxidative stress biomarkers, DNA damage and decreased muscle strength. The longer running distance and weight loss was observed in mice given IAP or subjected to IAP + SW compared to sedentary ones. Less heterogeneous microbial composition was noticed in sedentary obese colitis mice and this effect disappeared in IAP + SW mice. Absence of Alistipes , lower proportion of Turicibacter , Proteobacteria and Faecalibacterium , an increase in Firmicutes and Clostridium , a decrease in oxidative stress biomarkers, 8-OHdG content and proinflammatory cytokines were observed in IAP + SW mice. IAP supplementation in combination with moderate physical activity attenuates the severity of murine colitis complicated by obesity through a mechanism involving the downregulation of the intestinal cytokine/chemokine network and oxidative stress, the modulation of the gut microbiota and an improvement of muscle strength.

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine synthesized in vertebrates mainly in the pineal gland, and is known to be involved mainly in thermoregulation and control of the circadian rhythm. That indoleamine can affect the auto-, para- and endocrine pathways, regulating body functions and affecting the metabolism of animals and humans. In addition to the pineal gland, melatonin can be synthesized in many extra-pineal tissues, mainly in the gastrointestinal tract. Previous studies have shown that melatonin plays an important role in the defense system of the gastrointestinal mucosa, demonstrating a protective effect on the gastrointestinal tract and the acceleration of healing of chronic ulcers through the scavenging of reactive oxygen metabolites (ROS) and the activation of protective nitric oxide (NO) and vasodilator neuropeptides released from the sensory afferent neurons. The process of converting the melatonin precursor L-tryptophan into melatonin is already known, but not all aspects of this process for the synthesis of other metabolites of this pathway have been fully elucidated and this issue remains poorly understood. In this study, the conversion of L-tryptophan to melatonin and other metabolites was determined in gastric mucosa collected from rats with or without intragastric (i.g.) melatonin or L-tryptophan administration, both administered at a single dose of 50 mg/kg. For the determination of five metabolites of L-tryptophan: kynurenine, 5-hydroxytryptamine, 5-hydroxytryptophan, anthranilic acid, indole-3-acetic acid together with melatonin, we have modified the previously developed high-performance liquid chromatography (HPLC) method using a native fluorescence detection system and UV-VIS. The obtained results show that: 1) L-tryptophan is converted into melatonin in the gastric mucosa during the day, e.g. after eating a meal containing L-tryptophan, as it was imitated and confirmed by our study, in which this amino acid was administered directly to the stomach, 2) the gastric mucosa is capable of producing melatonin in much greater amounts than those recorded in the blood serum of rats given a single dose of L-tryptophan, and 3) apart from melatonin, the only serum levels of these five metabolites of the L-tryptophan metabolic pathway are detectable, while their level in the gastric mucosa is low and barely detectable under physiological conditions. Our present observations support the notion that the gastric mucosa is one of the main sources of melatonin production from L-tryptophan outside the pineal gland.

Although the natural niche for H. pylori (Hp) is the human stomach, for widespread infection to occur this microorganism may need to survive in the external environment. Molecular techniques such as polymerase (PCR) have revealed the presence of Hp DNA in water, indicating that this environment could act as a reservoir for this bacterium. The aim of this study was to analyse the occurrence of Hp in tap water from Cracow and to examine the relationship between 26 parameters and the presence of Hp DNA due to the lack of such information related to this issue in Poland. Additional aim of this study was to determine whether the correlation between Hp DNA detection and seasonal changes of water quality in 379 water samples collected from various water treatment plants (WTPs), could be found. Water samples were subjected to PCR for glmM and cagA genes. Ionic and organic composition of microelements were determined in accordance to Polish and ISO standards. The data obtained from tests show that 212 (55.96%) objects were Hp DNA (glmM) positive and among them 145 (68.40%) waters samples revealed expression of cagA. Linear Discriminant Analysis and Principal Component Analysis were used and provided that the selected variables (p < 0.05): colour, pH, conductivity at 25°C, chlorides, nitrites, nitrates, phosphates, chlorates, chlorites, sulphates, free chlorine, sodium, magnesium, potassium, calcium, organic carbon, trichloromethane, bromodichloromethane, dibromochloroethane, total iron, ammonium ion, and ƩTMHs distinguished the water samples that contain Hp DNA and do not contain Hp DNA. We conclude that the ionic and organic composition of microelements in water might influence the presence of Hp. Thus, determination of the selected microelements may indirectly indicate or sometimes predict the presence of Hp in drinking water.

Hydrogen sulfide (H 2 S) is an endogenously produced molecule with anti-inflammatory and cytoprotective properties. We aimed to investigate for the first time if a novel, esterase-sensitive H 2 S-prodrug, BW-HS-101 with the ability to release H 2 S in a controllable manner, prevents gastric mucosa against acetylsalicylic acid-induced gastropathy on microscopic and molecular levels. Wistar rats were pretreated intragastrically with vehicle, BW-HS-101 (0.5-50 μmol/kg) or its analogue without the ability to release H 2 S, BW-iHS-101 prior to ASA administration (125 mg/kg, intragastrically). BW-HS-101 was administered alone or in combination with nitroarginine (L-NNA, 20 mg/kg, intraperitoneally) or zinc protoporphyrin IX (10 mg/kg, intraperitoneally). Gastroprotective effects of BW-HS-101 were additionally evaluated against necrotic damage induced by intragastrical administration of 75% ethanol. Gastric mucosal damage was assessed microscopically, and gastric blood flow was determined by laser flowmetry. Gastric mucosal DNA oxidation and PGE 2 concentration were assessed by ELISA. Serum and/or gastric protein concentrations of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-13, VEGF, GM-CSF, IFN-γ, TNF-α, and EGF were determined by a microbeads/fluorescent-based multiplex assay. Changes in gastric mucosal iNOS, HMOX-1, SOCS3, IL1-R1, IL1-R2, TNF-R2, COX-1, and COX-2 mRNA were assessed by real-time PCR. BW-HS-101 or BW-iHS-101 applied at a dose of 50 μmol/kg protected gastric mucosa against ASA-induced gastric damage and prevented a decrease in the gastric blood flow level. H 2 S prodrug decreased DNA oxidation, systemic and gastric mucosal inflammation with accompanied upregulation of SOCS3, and EGF and HMOX-1 expression. Pharmacological inhibition of nitric oxide (NO) synthase but not carbon monoxide (CO)/heme oxygenase (HMOX) activity by L-NNA or ZnPP, respectively, reversed the gastroprotective effect of BW-HS-101. BW-HS-101 also protected against ethanol-induced gastric injury formation. We conclude that BW-HS-101, due to its ability to release H 2 S in a controllable manner, prevents gastric mucosa against drugs-induced gastropathy, inflammation and DNA oxidation, and upregulate gastric microcirculation. Gastroprotective effects of this H 2 S prodrug involves endogenous NO but not CO activity and could be mediated by cytoprotective and anti-inflammatory SOCS3 and EGF pathways.

Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most widely used classes of drugs and play a pivotal role in the therapy of numerous inflammatory diseases. However, the adverse effects of these drugs, especially when applied chronically, frequently affect gastrointestinal (GI) tract, resulting in ulceration and bleeding, which constitutes a significant limitation in clinical practice. On the other hand, it has been recently discovered that gaseous mediators nitric oxide (NO), hydrogen sulfide (H 2 S) and carbon monoxide (CO) contribute to many physiological processes in the GI tract, including the maintenance of GI mucosal barrier integrity. Therefore, based on the possible therapeutic properties of NO, H 2 S and CO, a novel NSAIDs with ability to release one or more of those gaseous messengers have been synthesized. Until now, both preclinical and clinical studies have shown promising effects with respect to the anti-inflammatory potency as well as GI-safety of these novel NSAIDs. This review provides an overview of the gaseous mediators-based NSAIDs along with their mechanisms of action, with special emphasis on possible implications for GI mucosal defense mechanisms., Competing Interests: JW was employed by Antibe Therapeutics, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Danielak, Wallace, Brzozowski and Magierowski.)

Intestinal alkaline phosphatase (IAP) is an essential mucosal defense factor involved in the process of maintenance of gut homeostasis. We determined the effect of moderate exercise (voluntary wheel running) with or without treatment with IAP on the course of experimental murine 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis by assessing disease activity index (DAI), colonic blood flow (CBF), plasma myokine irisin levels and the colonic and adipose tissue expression of proinflammatory cytokines, markers of oxidative stress (SOD2, GPx) and adipokines in mice fed a standard diet (SD) or high-fat diet (HFD). Macroscopic and microscopic colitis in sedentary SD mice was accompanied by a significant decrease in CBF, and a significant increase in the colonic expression of tumor necrosis factor-alpha (TNF-α), IL-6, IL-1β and leptin mRNAs and decrease in the mRNA expression of adiponectin. These effects were aggravated in sedentary HFD mice but reduced in exercising animals, potentiated by concomitant treatment with IAP, especially in obese mice. Exercising HFD mice demonstrated a substantial increase in the mRNA for adiponectin and a decrease in mRNA leptin expression in intestinal mucosa and mesenteric fat as compared to sedentary animals. The expression of SOD2 and GPx mRNAs was significantly decreased in adipose tissue in HFD mice, but these effects were reversed in exercising mice with IAP administration. Our study shows for the first time that the combination of voluntary exercise and oral IAP treatment synergistically favored healing of intestinal inflammation, strengthened the antioxidant defense and ameliorated the course of experimental colitis; thus, IAP may represent a novel adjuvant therapy to alleviate inflammatory bowel disease (IBD) in humans.

Metal-based carbon monoxide (CO)-releasing molecules have been shown to exert anti-inflammatory and anti-oxidative properties maintaining gastric mucosal integrity. We are interested in further development of metal-free CO-based therapeutics for oral administration. Thus, we examine the protective effect of representative CO prodrug, BW-CO-111, in rat models of gastric damage induced by necrotic ethanol or aspirin, a representative non-steroidal anti-inflammatory drug. Treatment effectiveness was assessed by measuring the microscopic/macroscopic gastric damage area and gastric blood flow by laser flowmetry. Gastric mucosal mRNA and/or protein expressions of HMOX1, HMOX2, nuclear factor erythroid 2-related factor 2, COX1, COX2, iNos , Anxa1 and serum contents of TGFB1, TGFB2, IL1B, IL2, IL4, IL5, IL6, IL10, IL12, tumor necrosis factor α , interferon γ , and GM-CSF were determined. CO content in gastric mucosa was assessed by gas chromatography. Pretreatment with BW-CO-111 (0.1 mg/kg, i.g.) increased gastric mucosal content of CO and reduced gastric lesions area in both models followed by increased GBF. These protective effects of the CO prodrug were supported by changes in expressions of molecular biomarkers. However, because the pathomechanisms of gastric damage differ between topical administration of ethanol and aspirin, the possible protective and anti-inflammatory mechanisms of BW-CO-111 may be somewhat different in these models., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Physical exercise is known to influence hormonal mediators of appetite, but the effect of short-term maximal intensity exercise on plasma levels of appetite hormones and cytokines has been little studied. We investigated the effect of a 30 s Wingate Test, followed by a postprandial period, on appetite sensations, food intake, and appetite hormones. Twenty-six physically active young males rated their subjective feelings of hunger, prospective food consumption, and fatigue on visual analogue scales at baseline, after exercise was completed, and during the postprandial period. Blood samples were obtained for the measurement of nesfatin-1, ghrelin, leptin, insulin, pancreatic polypeptide (PP), human growth factor (hGH) and cytokine interleukin-6 (IL-6), irisin and plasma lactate concentrations, at 30 min before exercise, immediately (210 s) after exercise, and 30 min following a meal and at corresponding times in control sedentary males without ad libitum meal intake, respectively. Appetite perceptions and food intake were decreased in response to exercise. Plasma levels of irisin, IL-6, lactate, nesfatin-1 and ghrelin was increased after exercise and then it was returned to postprandial/control period in both groups. A significant rise in plasma insulin, hGH and PP levels after exercise was observed while meal intake potentiated this response. In conclusion, an acute short-term fatiguing exercise can transiently suppress hunger sensations and food intake in humans. We postulate that this physiological response involves exercise-induced alterations in plasma hormones and the release of myokines such as irisin and IL-6, and supports the notion of existence of the skeletal muscle-brain-gut axis. Nevertheless, the detailed relationship between acute exercise releasing myokines, appetite sensations and impairment of this axis leading to several diseases should be further examined.

Helicobacter pylori ( Hp) -induced inflammatory reaction leads to a persistent disturbance of gastric mucosa and chronic gastritis evidenced by deregulation of tissue self-renewal and local fibrosis with the crucial role of epithelial-mesenchymal transition (EMT) in this process. As we reported before, Hp activated gastric fibroblasts into cells possessing cancer-associated fibroblast properties (CAFs), which secreted factors responsible for EMT process initiation in normal gastric epithelial RGM1 cells. Here, we showed that the long-term incubation of RGM1 cells in the presence of Hp -activated gastric fibroblast ( Hp -AGF) secretome induced their shift towards plastic LGR5 + /Oct4 high /Sox-2 high /c-Myc high /Klf4 low phenotype (l.t.EMT + RGM1 cells), while Hp -non-infected gastric fibroblast (GF) secretome prompted a permanent epithelial-myofibroblast transition (EMyoT) of RGM1 cells favoring LGR - /Oct4 high /Sox2 low /c-Myc low /Klf4 high phenotype (l.t.EMT - RGM1 cells). TGFβ1 rich secretome from Hp -reprogrammed fibroblasts prompted phenotypic plasticity and EMT of gastric epithelium, inducing pro-neoplastic expansion of post-EMT cells in the presence of low TGFβR1 and TGFβR2 activity. In turn, TGFβR1 activity along with GF-induced TGFβR2 activation in l.t.EMT - RGM1 cells prompted their stromal phenotype. Collectively, our data show that infected and non-infected gastric fibroblast secretome induces alternative differentiation programs in gastric epithelium at least partially dependent on TGFβ signaling. Hp infection-activated fibroblasts can switch gastric epithelium microevolution towards cancer stem cell-related differentiation program that can potentially initiate gastric neoplasm.

Barrett's esophagus (BE) is a premalignant condition caused by gastroesophageal reflux disease (GERD), where physiological squamous epithelium is replaced by columnar epithelium. Several in vivo and in vitro BE models were developed with questionable translational relevance when implemented separately. Therefore, we aimed to screen Gene Expression Omnibus 2R (GEO2R) databases to establish whether clinical BE molecular profile was comparable with animal and optimized human esophageal squamous cell lines-based in vitro models. The GEO2R tool and selected databases were used to establish human BE molecular profile. BE-specific mRNAs in human esophageal cell lines (Het-1A and EPC2) were determined after one, three and/or six-day treatment with acidified medium (pH 5.0) and/or 50 and 100 µM bile mixture (BM). Wistar rats underwent microsurgical procedures to generate esophagogastroduodenal anastomosis (EGDA) leading to BE. BE-specific genes (keratin ( KRT)1 , KRT4 , KRT5 , KRT6 A, KRT13 , KRT14 , KRT15 , KRT16 , KRT23 , KRT24, KRT7 , KRT8 , KRT18 , KRT20 , trefoil factor ( TFF ) 1 , TFF2 , TFF3 , villin ( VIL ) 1 , mucin ( MUC ) 2 , MUC3A/B , MUC5B , MUC6 and MUC13 ) mRNA expression was assessed by real-time PCR. Pro/anti-inflammatory factors (interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, tumor necrosis factor α, interferon γ, granulocyte-macrophage colony-stimulating factor) serum concentration was assessed by a Luminex assay. Expression profile in vivo reflected about 45% of clinical BE with accompanied inflammatory response. Six-day treatment with 100 µM BM (pH 5.0) altered gene expression in vitro reflecting in 73% human BE profile and making this the most reliable in vitro tool taking into account two tested cell lines. Our optimized and established combined in vitro and in vivo BE models can improve further physiological and pharmacological studies testing pathomechanisms and novel therapeutic targets of this disorder.

Gut-brain axis plays a central role in the regulation of stress related diseases such as irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). It is increasingly recognized that stress modulates gut microbiota community structure and activity and represents an important causal factor in dysbiosis. This study was designed to determine the effect of daily treatment with synbiotic (Syngut) containing inulin, Lactobacillus acidophilus, Bifidobacterium lactis W51, Lactobacillus plantarum W21 and Lactococcus lactis applied i.g. at a dose of 50 mg/kg i.g. on the colonic damage and colonic mucosal blood flow in rats with experimentally induced TNBS-colitis that were additionally exposed or not to acute stress (episodes of cold restraint stress every other day before colitis induction). Control rats received daily treatment with vehicle (saline, i.g.) or mesalazine (50 mg/kg-d i.g.), the standard drug recommended in therapy of IBD. At the termination of TNBS colitis, the histologic evaluation of colonic mucosa, mucosal malonyldialdehyde (MDA) level and plasma concentrations of proinflammatory cytokines (TNF-α, IL-1β) and adipokine adiponectin were assessed. the samples of colonic mucosa not involving colonic lesions and surrounding the flared mucosa were excised for the determination of mRNA expression for proinflammatory biomarkers TNF-α, IL-1β, IL-10 and COX-2 as well as antioxidazing factors SOD-1 and SOD-2. Finally, the gut microbial profiles were analyzed by 16S rRNA sequencing at phylum, family and genus level. Episodes of cold stress significantly aggravated the course of TNBS colitis, and significantly increased the release of proinflammatory cytokines as well as the significant increase in the MDA concentration has been observed as compared with non-stressed TNBS rats. These changes were followed by the significant fall in the CBF and plasma adiponectin levels and by the overexpression of mRNA of proinflammatory biomarkers. Synbiotic treatment with Syngut significantly reduced the area of colonic lesions observed macroscopically and microscopically in rats with TNBS colitis with or without exposure to cold stress, significantly increased the CBF, normalized plasma adiponectin levels and significantly attenuated the release and colonic expression of proinflammatory cytokines and biomarkers. the analysis of the gut microbiota showed a significant reduction of microbial diversity (Shannon index) in rats with TNBS colitis with or without exposure to stress. The therapy with Syngut failed to significantly affect the alpha diversity. At the phylum level, the significant rise in Proteobacteria has been observed in stressed rats with TNBS colitis and this effects was attenuated by treatment with Syngut. At family level, TNBS colitis alone or in combination with stress led to a significant decrease of SCFA producing bacterial taxa such as Ruminococaceae and Lachnospiraceae and Syngut counteracted this effect. We conclude that: 1) cold stress exacerbates the gastrointestinal inflammation in experimental colitis; 2) the synbiotic therapy with Syngut ameliorates the gut inflammation in rats with TNBS colitis combined with cold stress; 3) the beneficial effect of Syngut is accompanied by increase of anti-inflammatory taxa such as Ruminococaceae and Lachnospiraceae, and 4) the modulation of gut microbiota with Syngut alleviates stress-related intestinal inflammation suggesting a potential usefulness of synbiotic therapy in intestinal disorders accompanied by stress in patients with IBD.

Exposure to acidic gastric content due to malfunction of lower esophageal sphincter leads to acute reflux esophagitis (RE) leading to disruption of esophageal epithelial cells. Carbon monoxide (CO) produced by heme oxygenase (HMOX) activity or released from its donor, tricarbonyldichlororuthenium (II) dimer (CORM-2) was reported to protect gastric mucosa against acid-dependent non-steroidal anti-inflammatory drug-induced damage. Thus, we aimed to investigate if CO affects RE-induced esophageal epithelium lesions development. RE induced in Wistar rats by the ligation of a junction between pylorus and forestomach were pretreated i.g. with vehicle CORM-2; RuCl 3 ; zinc protoporphyrin IX, or hemin. CORM-2 was combined with NG-nitro-L-arginine (L-NNA), indomethacin, capsazepine, or capsaicin-induced sensory nerve ablation. Esophageal lesion score (ELS), esophageal blood flow (EBF), and mucus production were determined by planimetry, laser flowmetry, histology. Esophageal Nrf-2, HMOXs, COXs, NOSs, TNF-α and its receptor, IL-1 family and IL-1 receptor antagonist (RA), NF-κB, HIF-1α, annexin-A1, suppressor of cytokine signaling (SOCS3), TRPV1, c-Jun, c-Fos mRNA/protein expressions, PGE 2 , 8-hydroxy-deoxyguanozine (8-OHdG) and serum COHb, TGF-β1, TGF-β2, IL-1β, and IL-6 content were assessed by PCR, immunoblotting, immunohistochemistry, gas chromatography, ELISA or Luminex platform. Hemin or CORM-2 alone or combined with L-NNA or indomethacin decreased ELS. Capsazepine or capsaicin-induced denervation reversed CORM-2 effects. COHb blood content, esophageal HMOX-1, Nrf-2, TRPV1 protein, annexin-A1, HIF-1α, IL-1 family, NF-κB, c-Jun, c-Fos, SOCS3 mRNA expressions, and 8-OHdG levels were elevated while PGE 2 concentration was decreased after RE. CO donor-maintained elevated mucosal TRPV1 protein, HIF-1 α, annexin-A1, IL-1RA, SOCS3 mRNA expression, or TGF-β serum content, decreasing 8-OHdG level, and particular inflammatory markers expression/concentration. CORM-2 and Nrf-2/HMOX-1/CO pathway prevent esophageal mucosa against RE-induced lesions, DNA oxidation, and inflammatory response involving HIF-1α, annexin-A1, SOCS3, IL-1RA, TGF-β-modulated pathways. Esophagoprotective and hyperemic CO effects are in part mediated by afferent sensory neurons and TRPV1 receptors activity with questionable COX/PGE 2 or NO/NOS systems involvement., Competing Interests: None declared