Search

Ingestion of a corrosive substance may cause corrosive esophagitis. Curcumin has anti-inflammatory and mucosal protective effects. In this study, the effects of curcumin on the acute phase of corrosive esophagitis were investigated. Twenty-seven Wistar Albino rats were divided into four groups; sham (group I), control (group II), and experiment groups (group III, 100 mg/kg curcumin; group IV, 200 mg/kg curcumin). Forty percent sodium hydroxide solution was used to erode the esophagi of rats in groups other than the sham group. Curcumin was applied to animals in the experiment groups 10 min after the corrosion. After 24 h, animals were sacrificed, and esophagus samples were collected. According to the histopathological examination, the muscularis mucosa damage was regressed from 100% in group II to 71.4% in group III and 50% in group IV. Mild level of damage and collagen deposition in the tunica muscularis regressed from 66.7% of the animals in the control group to 42.9% in group III and to none in group IV. Further, an increase in submucosal collagen was present in all samples from groups II and III, while 83.3% of samples had an increase in submucosal collagen in group IV. There was a significant difference in the histopathological total score between the control group and group IV (p=0.02). The results showed that the administration of curcumin in a dose-dependent manner can relieve the acute phase of corrosive esophagitis., (© 2024. The Author(s).)

Objectives: Angico gum (AG) (Anadenanthera colubrina var. Cebil [Griseb.] Altschul) is utilized by some Brazilian communities to alleviate symptoms from gastroesophageal reflux disease. Here, we aimed to investigate the "in vitro" topical protective capacity of AG on human esophageal mucosa., Methods: Biopsies of the distal esophageal mucosa were collected from 35 patients with heartburn (24 non-erosive and 11 with erosive oesophagitis (EE)) and mounted in Üssing chambers. AG was applied topically, followed by exposure with acid solution (pH 2.0 or pH 1.0), where transepithelial electrical resistance (TER) and The transepithelial permeability for fluorescein was assessed. The incubation of the AG labeled with FITC in the esophageal mucosa was localized by fluorescence microscopy., Key Findings: Pretreatment with AG prevented the drop in TER induced by acid solution, as well as significantly decreases the fluorescein permeability in non-erosive patients. The protective effect of AG was sustained for up to 120 min both in biopsies of non-erosive and erosive esophagitis. Confocal microscope images showed mucosal luminal adherence of FITC-labeled AG., Conclusion: AG had a prolonged topical protective effect against acid solution in mucosal biopsies of patients with non-erosive and erosive esophagitis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Several features of drug-induced mucosal alterations have been observed in the upper gastrointestinal tract, i.e., the esophagus, stomach, and duodenum. These include pill-induced esophagitis, desquamative esophagitis, worsening of gastroesophageal reflux, chemotherapy-induced esophagitis, proton pump inhibitor-induced gastric mucosal changes, medication-induced gastric erosions and ulcers, pseudomelanosis of the stomach, olmesartan-related gastric mucosal inflammation, lanthanum deposition in the stomach, zinc acetate hydrate tablet-induced gastric ulcer, immune-related adverse event gastritis, olmesartan-asso-ciated sprue-like enteropathy, pseudomelanosis of the duodenum, and lanthanum deposition in the duodenum. For endoscopists, acquiring accurate knowledge regarding these diverse drug-induced mucosal alterations is crucial not only for the correct diagnosis of these lesions but also for differential diag-nosis of other conditions. This minireview aims to provide essential information on drug-induced mucosal alterations observed on esophagogastroduodenoscopy, along with representative endoscopic images., Competing Interests: Conflict-of-interest statement: Iwamuro M has received lecture fees from Otsuka Pharmaceutical Co., Ltd. and Ono Pharmaceutical Co., Ltd., as well as grants from Taisho Pharmaceutical Co., Ltd., Zeria Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Abbott Japan Co., Ltd. Kawano S has received lecture fees from Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Astellas Pharma Inc., AstraZeneca PLC, Viatris Inc., Zeria Pharmaceutical Co., Ltd., and EA Pharma Co., Ltd., along with grants from Taisho Pharmaceutical Co., Ltd., Zeria Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Abbott Japan Co., Ltd. Otsuka M has received lecture fees from Chugai Pharmaceutical Co., Ltd., Gilead Sciences, Inc., Merck & Co., Inc., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, AbbVie GK, EA Pharma Co., Ltd., and Kowa Company, Ltd., along with grants from Taisho Pharmaceutical Co., Ltd., Zeria Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Abbott Japan Co., Ltd., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

A device that can easily measure electrical impedance might be a helpful tool for investigating the pathophysiology of gastroesophageal reflux disease. The first aim of this study was to validate our newly developed bioelectrical admittance measurement (BAM) through in vitro experimentation. The second aim was to investigate whether evaluation of BAM by this measurement differed between patients with heartburn according to their response to proton pump inhibitor (PPI) therapy. Caco-2 cell monolayers and three-dimensional tissues were examined by BAM using a frequency response analyzer. BAM was also used to measure the impedance through cell layers. Subsequently, BAM was performed during endoscopy in 41 patients experiencing heartburn without esophageal mucosal breaks. After 2-wk administration of 20-mg rabeprazole twice daily, patient responses to PPI were classified as "good" or "poor" according to their clinical course. In each patient, histological alterations and gene expression levels of inflammation mediators and tight junction proteins were evaluated. Impedance profiles indicated that monolayer Caco-2 cells on top of eight-layered normal human dermal fibroblasts had the highest magnitude of impedance over the range of frequencies. In vivo results revealed that patients with good responses to PPI displayed significantly higher admittance. Severity of low-grade inflammation was significantly associated with esophageal wall admittance. Moreover, esophageal wall admittance may be more closely related to basal zone hyperplasia than dilatation of intercellular spaces. Thus, BAM may be able to detect abnormalities in the subepithelial layer of the esophagus. NEW & NOTEWORTHY Bioelectrical admittance measurement is a new method to evaluate esophageal mucosal permeability vertically during upper gastrointestinal endoscopy. Measurement of low-grade inflammation of the esophageal mucosa with electrical conductivity shows promise in assessing proton pump inhibitor responsiveness in patients with gastroesophageal reflux disease. As various gastrointestinal diseases are associated with changes in mucosal permeability, bioelectrical admittance measurement is expected to be clinically applied to therapeutic decision-making for these diseases in the future.

Purpose: In Japan, two courses of CDDP+5-FU (CF) therapy followed by surgery are accepted as a standard treatment for stage II/III esophageal cancer (EC) based on the results of the JCOG9907 trial. To gain a better survival, benefit especially for stage III patients in comparison with CF therapy, a three-arm phase III trial (neoadjuvant setting: CF vs. CF + radiation vs. DOC+CF [DCF]) is ongoing. We have aggressively performed DCF therapy for stage III or IV patients since October 2014. We herein review the outcomes of DCF therapy., Methods: We retrospectively reviewed the cases of 27 patients with stage III or IV EC (male, n = 24; female, n = 3; median age, 70.0 years) who received DCF therapy., Results: The response rate was 48.1%. Downstaging was achieved over the course of treatment in 14 patients (51.9%). Twenty-six patients transitioned to surgery, with 25 receiving R0 resection. DCF-treated patients who achieved downstaging showed significantly longer relapse-free survival (RFS) than those without downstaging (p = 0.0002). DCF-treated patients with a grade ≥ 1b histological effect showed significantly longer RFS than those with a grade < 1b effect (p = 0.0282). The multivariate analysis showed that downstaging was the only factor significantly associated with RFS in DCF-treated patients., Conclusions: DCF therapy for stage ≥ III esophageal carcinoma is both feasible and effective. These findings suggest that downstaging and the histological effect might predict the effects of DCF therapy for EC.

Background: Neoadjuvant chemoradiotherapy (nCRT), followed by surgery, is the current standard of care for patients with locally advanced esophageal squamous cell carcinoma. However, up to 30% of the patients do not respond to nCRT. Hence, a simple, cost-effective marker to predict response before initiation of nCRT is needed. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic marker in various cancers. However, its role as a predictive marker in patients with esophageal SCC planned for nCRT has not been prospectively analyzed., Materials and Methods: All consecutive patients with locally advanced (T1N1 and T2-T4a with or without nodal involvement) SCC planned for nCRT (CROSS protocol) followed by esophagectomy with total two field lymphadenectomy between December 2013 and December 2019 were included in this prospective analytical cohort study. NLR was calculated 1 week before starting the nCRT and was correlated with the histopathological response [Mandard tumor regression grade (TRG)]., Results: Of the 216 patients with esophageal cancer evaluated during the study period, 57 patients with SCC who fulfilled the inclusion criteria were included. A good pathologic response (TRG 1 and 2) to nCRT was seen in 28 (49.1%) patients. Using a ROC curve, the optimal cutoff value of pretherapy NLR for predicting good pathologic response was 2.33. With an NLR cutoff value of 2.33, 53.3% of patients had a good pathologic response to nCRT compared with 47.6% patients with NLR ≥ 2.33 (P = 0.77)., Conclusion: In patients with locally advanced esophageal SCC, NLR is not a useful marker to predict pathologic response to nCRT.

Hypergastrinemia has been associated with high-grade dysplasia and adenocarcinoma in patients with Barrett's esophagus, and experimental studies suggest proinflammatory and proneoplastic effects of gastrin on Barrett's esophagus. This is of potential concern, as patients with Barrett's esophagus are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK 2 receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in Barrett's esophagus. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with Barrett's esophagus without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/mm 2 , SD 620.7; placebo: +307.8 Ki67+ cells/mm 2 , SD 640.3; P = 0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype ( TFF2, MUC5B ) and certain cancer-associated markers ( REG3A, PAX9, MUC1 ), and decreased expression of intestinal markers MUC2, FABP1, FABP2 , and CDX1 No serious adverse events related to study drug occurred. The gastrin/CCK 2 receptor antagonist netazepide did not reduce cellular proliferation in patients with nondysplastic Barrett's esophagus. Further research should focus on the biological effects of gastrin in Barrett's esophagus. Prevention Relevance: Treatment of patients with Barrett's esophagus with a gastrin/CCK 2 receptor antagonist did not have obvious chemopreventive effects., (©2021 American Association for Cancer Research.)

Acellular scaffolds from decellularized donor organs are showing promising clinical results in tissue and organ repair and regeneration. A successful decellularization process is determined by (a) its capability to decellularize complete organs of large animals, (b) retention of the extracellular matrix (ECM) structures and morphologies, and (c) minimal loss of ECM proteins. In this study, porcine esophagi were perfused in full thickness with 0.25% w/v sodium dodecyl sulfate at perfusion rates 0.1-0.2 ml/min for up to 5 days. Decellularized tissues were characterized for their residual DNA, histological staining for their matrix structures, immunohistochemical staining for collagen type IV and laminin, and scanning electron microscopy for structural integrity. Our results showed that full thickness esophageal tissues treated using the horizontal perfusion setup were decellularized with good structural and biochemical integrity in the ECM. Residual DNA content in decellularized tissues was found to be 36 ± 12 ng/mg of tissues (n = 6) which was significantly lower than that of native tissues (p = .00022). Our study showed that the organ must be decellularized in full thickness and perfusion pressure must be controlled to minimize radial expansion. These factors were found to be critical in preserving the folded mucosa in the decellularized tissues., (© 2020 Wiley Periodicals LLC.)

Context: Daidzein is a secondary metabolite derived from plants, has a flavonoid structure and is known for its protective activity in gastrointestinal disorders. Objective: The current work determines the preventive effect of daidzein against injury in the esophagus mucosa induced by esophageal reflux (RE) in an animal model. Methods: Adult male Wistar rats were classified into six groups: normal control, ER + different doses of daidzein and ER + omeprazole. RE was induced in all animals except controls and supplemented with daidzein and standard drugs orally for 6 hours. Serum and tissue were used for further biochemical parameters. Results: Daidzein as a flavonoid has antioxidant properties and shows in vitro antioxidant activity. The outcomes also reveal an elevation in lipid peroxidation and a decline in the levels of sulphhydryl groups and glutathione, along with the depletion in the activities of enzymatic antioxidants in the oxidative stress state. In a dose-dependent manner daidzein and omeprazole amended all macroscopic and biochemical variations and protected against the raised level of hydrogen peroxide (H₂O₂), calcium and free iron levels in esophageal tissue induced during RE. It also improved the expression and level of proinflammatory cytokines. Conclusion : The finding reports that daidzein has a potential to show a shielding effect against esophagus damage induced by RE in rats, at least in part via alteration of inflammatory cytokines.

Introduction: With increasing advances in minimally invasive endoscopic therapies and endoscopic resection techniques for luminal disease, there is an increased risk of post-procedure bleeding. This can contribute to significant burden on patient's quality of life and health resources when reintervention is required. Hemospray (Cook Medical, North Carolina, USA) is a novel haemostatic powder licensed for gastrointestinal bleeding. The aim of this single-arm, prospective, non-randomised multicentre international study is to look at outcomes in patients with upper gastrointestinal bleeds following elective endoscopic therapy treated with Hemospray to achieve haemostasis., Methods: Data was prospectively collected on the use of Hemospray from 16 centres (January 2016-November 2019). Hemospray was used during the presence of progressive intraprocedural bleeding post-endoscopic therapy as a monotherapy, dual therapy with standard haemostatic techniques or rescue therapy once standard methods had failed. Haemostasis was defined as the cessation of bleeding within 5 min of the application of Hemospray. Re-bleeding was defined as a sustained drop in haemoglobin (>2 g/l), haematemesis or melaena with haemodynamic instability after the index endoscopy., Results: A total of 73 patients were analysed with bleeding post-endoscopic therapy. The median Blatchford score at baseline was five (interquartile range 0-9). The median Rockall score was six (interquartile range 5-7). Immediate haemostasis following the application of Hemospray was achieved in 73/73 (100%) of patients. Two out of 57 (4%) had a re-bleed post-Hemospray, one was following oesophageal endoscopic mucosal resection and the other post-duodenal endoscopic mucosal resection. Both patients had a repeat endoscopy and therapy within 24 h. Re-bleeding data was missing for 16 patients, and mortality data was missing for 14 patients. There were no adverse events recorded in association with the use of Hemospray., Conclusion: Hemospray is safe and effective in achieving immediate haemostasis following uncontrolled and progressive intraprocedural blood loss post-endoscopic therapy, with a low re-bleed rate.

The role of weak acids with pH values in the range of 4-7 has been implicated in the symptoms of gastroesophageal reflux disease (GERD). Prostaglandin E 2 (PGE 2 ) is associated with heartburn symptom in GERD patients; however, the precise productive mechanisms remain unclear. In this study, we revealed that exposure to weak acids increases PGE 2 production with a peak at pH 4-5, slightly in human normal oesophageal cells (Het-1A), and robustly in oesophageal squamous carcinoma cells (KYSE-270). Release of PGE 2 from the oesophageal mucosa was augmented by weak acid treatment in rat. Chenodeoxycholic acid (CDCA), a bile acid, upregulated cyclooxygenase-2 (COX-2) expression in Het-1A and KYSE-270 and induced PGE 2 production in KYSE-270 cells. Weak acid-induced PGE 2 production was significantly inhibited by cytosolic phospholipase A2 (cPLA2), ERK, and transient receptor potential cation channel subfamily V member 4 (TRPV4), a pH-sensing ion channel, inhibitors. Hangeshashinto, a potent inhibitor of COX-2, strongly decreased weak acid- and CDCA-induced PGE 2 levels in KYSE-270. These results indicated that weak acids induce PGE 2 production via TRPV4/ERK/cPLA2 in oesophageal epithelial cells, suggesting a role in GERD symptoms like heartburn. Interventions targeting pH values up to 5 may be necessary for the treatment of GERD.

Gastroesophageal reflux disease (GERD) is a common digestive disorder that causes esophagitis and injuries to the esophageal mucosa. GERD symptoms are recurrent during pregnancy and their treatment is focused on lifestyle changes and nonprescription medicines. The aim of this study was to characterize the mechanism of action of a new patented medical device, an oral formulation containing hyaluronic acid, rice extract, and amino acids dispersed in a bioadhesive polymer matrix, by assessing its protective effects in in vitro and ex vivo models of esophageal mucosa damage. Acidic bile salts and pepsin cocktail (BSC) added to CP-A and COLO-680 N esophagus cells were used as an in vitro GERD model to evaluate the binding capacities, anti-inflammatory effects and reparative properties of the investigational product (IP) in comparison to a viscous control. Our results showed that the IP prevents cell permeability and tight junction dysfunction induced by BSC. Furthermore, the IP was also able to down-regulate IL-6 and IL-8 mRNA expression induced by BSC stimulation and to promote tissue repair and wound healing. The results were confirmed by ex vivo experiments in excised rat esophagi through the quantification of Evans Blue permeability assay. These experiments provided evidence that the IP is able to bind to the human esophagus cells, preventing the damage caused by gastroesophageal reflux, showing potential anti-irritative, soothing, and reparative properties., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The fabrication and characterization of ball-milling modified glutinous rice starch (MGRS):chitosan (CS) composite films were demonstrated. Effect of CS ratios (2:1, 1:1, 1:2 MGRS:CS) on the film properties was investigated. Lidocaine hydrochloride was used as a model hydrophilic drug. ATR-FTIR confirmed hydrogen bond formation between MGRS and CS. XRD indicated an amorphous state of all fabricated films. The uniform and comparable thickness, weight, and drug contents of all fabricated films were obtained. The presence of CS did not affect the mucoadhesiveness of MGRS films. The increase in tensile strength and decreases in elongation and folding endurance were observed with 1:2 MGRS:CS films. The film swelling and drug release decreased with the CS ratio. Drug permeation across porcine mucosa indicated the enhancement effect of CS, whereby the permeation flux of 1:2 MGRS:CS composite increased by 3 folds. In conclusion, the MGRS:CS composite could be useful for buccal delivery of hydrophilic drug., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Eosinophilic esophagitis (EoE) is an emergent chronic disease of the esophagus. The immunopathological process in EoE is characterized by Th2 immune response and prominent eosinophilic influx, in response to common food allergens. The classical treatment consists of allergen elimination diet and systemic/topical corticosteroid therapy. Nevertheless, patients do not always comply to treatment, and the prolonged corticosteroid therapy can cause side effects, therefore, there is an immediate need for new therapeutic approach for EoE. Disodium cromoglicate (DSCG) is a substance broadly used in allergic asthma treatment, and a well-known mast cell activation stabilizer. However, its effect in EoE have not been evaluated yet. This study aimed to assess the effects of DSCG treatment in an EoE experimental model. Male Balb/C mice were subcutaneously sensitized for five days with OVA, and subsequently orally OVA-challenged, DSCG administration was performed between the OVA-challenges. DSCG treatment not only reduced eosinophilic and mast cell influx, as well as reduced fibrosis. In addition, tslp, GATA 3, IL-5, FoxP 3 and IL-10 mRNA expression were reduced in esophageal mucosa, associated with lower Th2 (CD3 + CD4 + GATA3 + IL4 + ) and B cells (CD19 + CD40 + ) number in peripheral lymphoid organs. In conclusion, the data demonstrate DSCG treatment was effective in reducing mast cell activation and Th2 immune response, important immunopathological EoE features. Therefore, the use of DSCG as an EoE treatment can be considered a promising therapeutic approach to treat this disease., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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

Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2'-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention., (© The Author(s) 2019. Published by Oxford University Press.)

Keratinocytes take up serum-derived retinol (vitamin A) and metabolize it to all-trans-retinoic acid (atRA), which binds to the nuclear retinoic acid receptor (RAR). We previously reported that serum-affected keratinocyte differentiation and function; namely, it inhibited keratinization, decreased loricrin (LOR) and claudin (CLDN) 1 expression, increased keratin (K) 4 and CLDN4 levels, and reduced paracellular permeability in three-dimensional (3D) cultures of mouse keratinocytes (COCA). Contrarily, RAR inhibition reversed these changes. Here, we aimed to examine whether atRA exerted the same effects as serum, and whether it was involved in the differential oral mucosa keratinization among animal species. Porcine oral mucosal keratinocytes, which form non-keratinized epithelium in vivo, established keratinized epithelium in 3D cultures. Both mouse and porcine sera induced non-keratinized epithelium at 0.1% in COCA 3D cultures. Although atRA caused the same changes as serum, its effective concentration differed. atRA inhibited keratinization at 0.1 nM and 1 nM in porcine or human keratinocytes and COCA, respectively. Furthermore, atRA upregulated CLDN7 in the cytoplasm but not in cell-cell contacts. These atRA-induced changes were reverted by RAR inhibition. The results indicate that serum-induced changes are probably due to the effect of serum-derived atRA, and that mouse keratinocytes require higher atRA concentrations to suppress keratinization than porcine and human keratinocytes. We propose that the lower susceptibility of mouse keratinocytes to atRA, rather than a lower retinol concentration, is a possible reason for the keratinization of mouse oral mucosal epithelium.

Salivary epidermal growth factor (EGF) plays an important role in the maintenance of the oral and gastro-esophageal mucosa. Sialoadenectomy delays healing of oral wounds and affects lingual papillae. In this work, we aimed to determine the effect of EGF deficiency induced by sialoadenectomy and evaluate the effect of exogenous EGF administration on the lingual papillae and taste buds in rats. Thirty male adult Wistar albino rats were equally divided into 3 groups; sham-operated control group, sialoadenectomy group and group of sialoadenectomy + EGF. EGF was given 8 weeks after sialoadenectomy in a dose of 1 μg /ml/day in drinking water for 2 weeks. The anterior two-thirds of the tongue was dissected and cut longitudinally into two halves; one half for light microscope and the other for electron microscope examinations. Saliva and blood were collected to determine salivary and plasma EGF. Our results revealed that sialoadenectomy significantly reduced plasma and saliva levels of EGF which resulted in severe disruption of the architecture of lingual papillae. These changes were effectively improved by the exogenous EGF administration. In conclusion, EGF supplementation reversed the effects of sialoadenectomy and restored almost normal architecture of lingual papillae and taste buds., Competing Interests: Declaration of Competing Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Esophageal injury from acid exposure related to gastroesophageal reflux disease is a common problem and a risk factor for development of Barrett's esophagus and esophageal adenocarcinoma. Our previous work highlights the benefits of using porcine esophagus to study human esophageal disease because of the similarities between porcine and human esophagus. In particular, esophageal submucosal glands (ESMGs) are present in human esophagus and proximal porcine esophagus but not in rodent esophagus. Although CFTR is expressed in the ducts of ESMGs, very little is known about CFTR and alternate anion channels, including ClC-2, in the setting of acid-related esophageal injury. After finding evidence of CFTR and ClC-2 in the basal layers of the squamous epithelium, and in the ducts of the ESMGs, we developed an ex vivo porcine model of esophageal acid injury. In this model, esophageal tissue was placed in Ussing chambers to determine the effect of pretreatment with the ClC-2 agonist lubiprostone on tissue damage related to acid exposure. Pretreatment with lubiprostone significantly reduced the level of acid injury and significantly augmented the recovery of the injured tissue ( P < 0.05). Evaluation of the interepithelial tight junctions showed well-defined membrane localization of occludin in lubiprostone-treated injured tissues. Pretreatment of tissues with the Na + -K + -2Cl - cotransporter inhibitor bumetanide blocked lubiprostone-induced increases in short-circuit current and inhibited the reparative effect of lubiprostone. Furthermore, inhibition of ClC-2 with ZnCl 2 blocked the effects of lubiprostone. We conclude that ClC-2 contributes to esophageal protection from acid exposure, potentially offering a new therapeutic target. NEW & NOTEWORTHY This research is the first to describe the presence of anion channels ClC-2 and CFTR localized to the basal epithelia of porcine esophageal mucosa and the esophageal submucosal glands. In the setting of ex vivo acid exposure, the ClC-2 agonist lubiprostone reduced acid-related injury and enhanced recovery of the epithelial barrier. This work may ultimately provide an alternate mechanism for treating gastroesophageal reflux disease.

Mixed acidic-alkaline refluxate is a major pathogenic factor in chronic esophagitis progressing to Barrett's esophagus (BE). We hypothesized that epidermal growth factor (EGF) can interact with COX-2 and peroxisome proliferator-activated receptor-γ (PPARγ) in rats surgically prepared with esophagogastroduodenal anastomosis (EGDA) with healthy or removed salivary glands to deplete salivary EGF. EGDA rats were treated with 1 ) vehicle, 2 ) EGF or PPARγ agonist pioglitazone with or without EGFR kinase inhibitor tyrphostin A46, EGF or PPARγ antagonist GW9662 respectively, 3 ) ranitidine or pantoprazole, and 4 ) the selective COX-2 inhibitor celecoxib combined with pioglitazone. At 3 mo, the esophageal damage and the esophageal blood flow (EBF) were determined, the mucosal expression of EGF, EGFR, COX-2, TNFα, and PPARγ mRNA and phospho-EGFR/EGFR protein was analyzed. All EGDA rats developed chronic esophagitis, esophageal ulcerations, and intestinal metaplasia followed by a fall in the EBF, an increase in the plasma of IL-1β, TNFα, and mucosal PGE 2 content, the overexpression of COX-2-, and EGF-EGFR mRNAs, and proteins, and these effects were aggravated by EGF and attenuated by pioglitazone. The rise in EGF and COX-2 mRNA was inhibited by pioglitazone but reversed by pioglitazone cotreated with GW9662. We conclude that 1 ) EGF can interact with PG/COX-2 and the PPARγ system in the mechanism of chronic esophagitis; 2 ) the deleterious effect of EGF involves an impairment of EBF and the overexpression of COX-2 and EGFR, and 3 ) agonists of PPARγ and inhibitors of EGFR may be useful in the treatment of chronic esophagitis progressing to BE. NEW & NOTEWORTHY Rats with EGDA exhibited chronic esophagitis accompanied by a fall in EBF and an increase in mucosal expression of mRNAs for EGF, COX-2, and TNFα, and these effects were exacerbated by exogenous EGF and reduced by removal of a major source of endogenous EGF with salivectomy or concurrent treatment with tyrphostin A46 or pioglitazone combined with EGF. Beneficial effects of salivectomy in an experimental model of BE were counteracted by PPARγ antagonist, whereas selective COX-2 inhibitor celecoxib synergistically with pioglitazone reduced severity of esophageal damage and protected esophageal mucosa from reflux. We propose the cross talk among EGF/EGFR, PG/COX-2, and proinflammatory cytokines with PPARγ pathway in the mechanism of pathogenesis of chronic esophagitis progressing to BE and EAC.

The frequency of esophageal adenocarcinoma is rising despite widespread use of proton pump inhibitors (PPIs), which heal reflux esophagitis but do not prevent reflux of weakly acidic gastric juice and bile in Barrett's esophagus patients. We aimed to determine if weakly acidic (pH 5.5) bile salt medium (WABM) causes DNA damage in Barrett's cells. Because p53 is inactivated frequently in Barrett's esophagus and p38 can assume p53 functions, we explored p38's role in DNA damage response and repair. We exposed Barrett's cells with or without p53 knockdown to WABM, and evaluated DNA damage, its response and repair, and whether these effects are p38 dependent. We also measured phospho-p38 in biopsies of Barrett's metaplasia exposed to deoxycholic acid (DCA). WABM caused phospho-H2AX increases that were blocked by a reactive oxygen species (ROS) scavenger. WABM increased phospho-p38 and reduced bromodeoxyuridine incorporation (an index of S phase entry). Repair of WABM-induced DNA damage proceeded through p38-mediated base excision repair (BER) associated with reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease I (Ref-1/APE1). Cells treated with WABM supplemented with ursodeoxycholic acid (UDCA) exhibited enhanced p38-mediated responses to DNA damage. All of these effects were observed in p53-intact and p53-deficient Barrett's cells. In patients, esophageal DCA perfusion significantly increased phospho-p38 in Barrett's metaplasia. WABM exposure generates ROS, causing oxidative DNA damage in Barrett's cells, a mechanism possibly underlying the rising frequency of esophageal adenocarcinoma despite PPI usage. p38 plays a central role in oxidative DNA damage response and Ref-1/APE1-associated BER, suggesting potential chemopreventive roles for agents like UDCA that increase p38 activity in Barrett's esophagus. NEW & NOTEWORTHY We found that weakly acidic bile salt solutions, with compositions similar to the refluxed gastric juice of gastroesophageal reflux disease patients on proton pump inhibitors, cause oxidative DNA damage in Barrett's metaplasia that could contribute to the development of esophageal adenocarcinoma. We also have elucidated a critical role for p38 in Barrett's metaplasia in its response to and repair of oxidative DNA damage, suggesting a potential chemopreventive role for agents like ursodeoxycholic acid that increase p38 activity in Barrett's esophagus.

Background & Aims: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE., Methods: We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety., Results: The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P = .0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic reference score by 1.6 (P = .0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P < .0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group)., Conclusions: In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Drug-induced esophagitis is an uncommon diagnosis in the pediatric population. The following is a report of six adolescents with L-arginine-induced esophagitis., Case Reports: All patients were under treatment with L-arginine for short stature. After using the prescribed medication for 1-3 months, all cases started with severe retrosternal pain, odynophagia, and dysphagia. The upper gastrointestinal endoscopies showed ulcers located in the mid esophageal mucosa., Conclusions: In the presence of acute severe odynophagia, dysphagia, and retrosternal pain, drug-induced esophagitis should be considered as a possible diagnosis. Treatment includes liquid diet, pain control, sucralfate, omeprazole, and interruption of L-arginine. In addition, the physician should explain preventive measures focused on patient and family education on the drug side effects and precise instructions on how to take medications, as well as a careful balance of risk and benefits of any medication. At present, there are no clinical trials that support the use of L-arginine in treatment of short stature., (Copyright: © 2019 Permanyer.)

This study aimed to investigate a standardized biopolymer, cashew gum (CG), in human oesophageal mucosa and mice with experimentally-induced non-erosive reflux disease (NERD). Human oesophageal biopsies from NERD patients were collected to evaluate the mucosal protection of CG through transepithelial electrical resistance (TER), mucosal permeability, and mucoadhesiveness tests. A surgical model of NERD in mice was induced, and barrier functions followed by suggestive oesophageal inflammatory hallmarks were evaluated. Pre-coating of CG was effective in human oesophageal mucosa by attenuating drop of TER and mucosal permeability. Labelled-CG adheres to human oesophageal mucosa for up to 1 h. In animal studies, CG improved parameters of barrier function (TER and mucosal permeability) in distal oesophagus mucosa. CG also promoted sequential support by reducing inflammatory hallmarks of oesophageal damage. CG confers topical oesophageal mucosal protection due to its mucoadhesiveness and anti-inflammatory profile. Long-duration mucoprotective products can be further explored as first-line/adjuvant NERD therapy., (Copyright © 2019. Published by Elsevier Ltd.)

Purpose: The optimal treatment for locally advanced GEJ and cardia adenocarcinoma is controversial. Several studies have shown that treating these patients with neoadjuvant chemoradiotherapy followed by surgery leads to survival benefits, and there are also studies that have declared conflicting results. It seems that there is still room for discussion. We calculated the survival rates and pathologic responses in our patients with characteristics which we mentioned above., Methods: Patients with locally advanced, non-metastatic GEJ and cardia adenocarcinomas (only patients with Siewert's type I and II), who were referred to Imam Khomeini hospital (Institute of cancer) between 2005 and 2014 and received neoadjuvant chemoradiation and underwent surgery were enrolled in this retrospective cohort study. Evaluations were done every 3 months., Results: Thirty-two patients enrolled in this study. Median follow up time was 23 months (Reverse Kaplan-Meier method). The rates of 1-year survival, 2-year survival, 3-year survival, 4-year survival, and 5-year survival were 75%, 52%, 52%, 37%, and 37%, respectively. No local recurrences occurred among patients; however, four patients experienced distal recurrence in the following locations: two cases (6.3%) in the liver, one case (3.1%) in the lung, and one case (3.1%) in the peritoneum. The rate of complete pathologic response (T 0 N 0 ) was 21.9%., Conclusions: Neoadjuvant chemoradiation in patients with locally advanced GEJ and cardia adenocarcinoma will lead to a survival benefit.

Gastro-esophageal reflux disease is one of the most common disorders in gastroenterology. The aim of this work was to investigate the protection of isorhamnetin against esophageal mucosal injury in rats with chronic reflux esophagitis (RE). Chronic RE model was established through fundus ligation and partial obstruction of the pylorus in rats. Then, the rats were treated with isorhamnetin (5 mg/kg) daily for a period of 14 days. Through histological and gross assessment, it was found that administration of isorhamnetin alleviated esophageal mucosal injury in RE rats. Treatment of RE rats with isorhamnetin improved esophageal barrier function, through upregulating proteins expression of occludin and zonula occludens-1 (ZO-1) and downregulating proteins expression of matrix matalloproteinases-3 (MMP3) and -9. Administration of isorhamnetin decreased CD68-positive cells and mRNA levels of IL-6, TNF-α, and IL-1β in the esophagus of RE rats. Administration of isorhamnetin downregulated inducible nitric oxide synthase (iNOS) protein expression and decreased production of nitric oxide (NO) and 3-nitrotyrosin in the esophagus of RE rats. Administration of isorhamnetin enhanced heme oxygenase-1 (HO-1) activities and reduced malondialdehyde (MDA) levels in esophagus of RE rats. Additionally, treatment with isorhamnetin inhibited p38 MAPK and NFκB activation in RE esophagus. In conclusion, isorhamnetin attenuated esophageal mucosal injury in rats with chronic RE, possibly by suppressing formation of cytokines and infiltration of inflammatory cells, inhibiting p38 and NFκB pathways, and enhancing HO-1 activity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The prostaglandin D 2 receptor DP2 has been implicated in eosinophil infiltration and the development of eosinophilic esophagitis (EoE)., Aims and Methods: In this study, we investigated an involvement of PGE 2 (EP1-EP4) and PGD 2 (DP1) receptors in EoE by measuring their expression in peripheral blood eosinophils and esophageal mucosal biopsies of EoE patients and by performing migration and adhesion assays with eosinophils from healthy donors., Results: Expression of EP2 and EP4, but not EP1 and EP3, was decreased in blood eosinophils of patients with EoE vs. control subjects. Adhesion of eosinophils to esophageal epithelial cells was decreased by EP2 receptor agonist butaprost and EP4 agonist ONO-AE1-329, whereas DP1 agonist BW245C increased adhesion. In chemotaxis assays with supernatant from human esophageal epithelial cells, only ONO-AE1-329 but not butaprost or BW245C inhibited the migration of eosinophils. Expression of EP and DP receptors in epithelial cells and eosinophils was detected in sections of esophageal biopsies from EoE patients by immunohistochemistry. qPCR of biopsies from EoE patients revealed that gene expression of EP4 and DP1 was the highest among PGE 2 and PGD 2 receptors. Esophageal epithelial cells in culture showed high gene expression for EP2 and EP4. Activation of EP2 and EP4 receptors decreased barrier integrity of esophageal epithelial cells in impedance assays., Conclusions: Activation of EP2 and EP4 receptors may inhibit eosinophil recruitment to the esophageal mucosa. However, their activation could negatively affect esophageal barrier integrity suggesting that eosinophilic rather than epithelial EP2 and EP4 have a protective role in EoE.

There is an increasing prevalence of esophageal diseases but intact human tissue platforms to study esophageal function, disease mechanisms, and the interactions between cell types in situ are lacking. To address this, we utilized full thickness human donor esophagi to create and validate the ex vivo function of mucosa and smooth muscle (n = 25). Explanted tissue was tested for contractile responses to carbachol and histamine. We then treated ex vivo human esophageal mucosa with a cytokine cocktail to closely mimic the Th2 and inflammatory milieu of eosinophilic esophagitis (EoE) and assessed alterations in smooth muscle and extracellular matrix function and stiffening. We found that full thickness human esophagus as well as the individual layers of circular and longitudinal muscularis propria developed tension in response to carbachol ex vivo and that mucosa demonstrated squamous cell differentiation. Treatment of mucosa with Th2 and fibrotic cytokines recapitulated the majority of the clinical Eosinophilic Esophagitis Diagnostic Profile (EDP) on fluidic transcriptional microarray. Transforming growth factor-beta-1 (TGFβ1) increased gene expression of fibronectin, smooth muscle actin, and phospholamban (p < 0.001). The EoE cocktail also increased stiffness and decreased mucosal compliance, akin to the functional alterations in EoE (p = 0.001). This work establishes a new, transcriptionally intact and physiologically functional human platform to model esophageal tissue responses in EoE.

Sucralfate is effective for the treatment of gastric and duodenal ulcers owing to its protective gel-forming ability. However, the mechanism by which sucralfate protects the oesophageal mucosa against reflux oesophagitis has not been clarified. We aimed to investigate the mechanisms of action of sucralfate and sucrose octasulfate (SOS), a component of sucralfate. SOS and sucralfate were administered to oesophagitis-induced rats, and the ulcer lesion size was macroscopically examined and scored. Effective pepsin activity in the gastric juices obtained from the animal model was evaluated by a casein digestion test. Sucralfate and SOS improved the pathology scores in a dose-dependent manner, whereas gastric juice pepsin activity was not impaired by therapeutic doses of SOS. As SOS lacks the ability to form a thick gel layer by polymerisation, we examined the distribution of SOS in the mucosal lumen by imaging mass spectrometry (IMS) to determine whether SOS directly adheres to the mucosal surface. A clear homogeneous thin-layer SOS film (>100 μm thick) was visualized on the oesophageal mucosal surface. Moreover, this SOS film formation was enhanced at ulcer lesion sites. Taken together, SOS appears to protect oesophageal mucosa against reflux oesophagitis via thin-layer formation on the mucosal surface.

The aim of the present work was to load a Hibiscus sabdariffa (HS) hydroalcoholic extract into in situ gelling formulations for the treatment of oral mucositis and esophagitis. Such formulations, selected as the most promising options in a previous work of ours, were composed by κ-carrageenan (κ-CG), a sulfated marine polymer able to gelify in presence of saliva ions, hydroxypropyl cellulose (HPC), used as mucoadhesive agent, and CaCl₂, salt able to enhance the interaction κ-CG/saliva ions. HS extract, which is rich in phytochemicals such as polyphenols, polysaccharides and organic acids, was selected due to its antioxidant and anti-inflammatory properties. For HS extraction, three different methodologies (maceration, Ultrasound Assisted Extraction (UAE) and Microwave Assisted Extraction (MAE)) were compared in terms of extraction yield and extract antioxidant activity, revealing that MAE was the best procedure. Rheological and mucoadhesive properties of HS-loaded formulations were investigated. Such formulations were characterized by a low viscosity at 25 °C, guaranteeing an easy administration, a proper in situ gelation behavior and marked elastic and mucoadhesive properties at 37 °C, functional to a protective action towards the damaged mucosa. Finally, the biocompatibility and the proliferative effect of HS-loaded formulations, as well as their antioxidant and anti-inflammatory properties, were proved in vitro on human dermal fibroblasts.

Background: The caustic ingestion continues to be a major problem worldwide especially in developing countries. The long-term complications include stricture and increased life time risk of oesophageal carcinoma. Patients suffered from corrosive induced oesophageal strictures have more than a 1000-fold risk of developing carcinoma of the oesophagus., Aim: To determine the possibility of oesophageal mucosal dysplasia after prolonged dilatation in post corrosive stricture., Methods: This observational study was conducted at the Paediatric Endoscopy Unit in Cairo University Children's Hospital. It included children of both sexes older than 2 years of age who had an established diagnosis of post-corrosive oesophageal stricture and repeated endoscopic dilatation sessions for more than 6 mo. All patients were biopsied at the stricture site after 6 mo of endoscopic dilatation. A histopathological examination of an oesophageal mucosal biopsy was performed for the detection of chronic oesophagitis, inflammatory cellular infiltration and dysplasia., Results: The mean age of the enrolled children was 5.9 ± 2.6 years; 90% of the patients had ingested an alkaline corrosive substance (potash). The total number of endoscopic dilatation sessions were ranging from 16 to 100 with mean number of sessions was 37.2 ± 14.9. Histopathological examination of the specimens showed that 85% of patients had evidence of chronic oesophagitis (group A) in the form of basal cell hyperplasia, hyperkeratosis and subepithelial fibrosis. Thirteen percent of the patients had evidence of reactive atypia (group B) in the form of severe neutrophilic intraepithelial inflammatory cellular infiltration, and 2 patients (2%) had mild squamous dysplasia (group C); we rebiopsied these two patients 6 mo after the initial pathological assessment, guided by chromoendoscopy by Lugol's iodine., Conclusion: The histopathology of oesophageal mucosal biopsies in post-corrosive patients demonstrates evidence of chronic oesophagitis, intraepithelial inflammatory cellular infiltration and dysplasia. Dysplasia is one of the complications of post-corrosive oesophageal stricture., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report.

Pendrin (SLC26A4), a Cl - /anion exchanger, is expressed at high levels in kidney, thyroid, and inner ear epithelia, where it has an essential role in bicarbonate secretion/chloride reabsorption, iodide accumulation, and endolymph ion balance, respectively. Pendrin is expressed at lower levels in other tissues, such as airways and esophageal epithelia, where it is transcriptionally regulated by the inflammatory cytokines interleukin (IL)-4 and IL-13 through a signal transducer and activator of transcription 6 (STAT6)-mediated pathway. In the airway epithelium, increased pendrin expression during inflammatory diseases leads to imbalances in airway surface liquid thickness and mucin release, while, in the esophageal epithelium, dysregulated pendrin expression is supposed to impact the intracellular pH regulation system. In this review, we discuss some of the recent findings on interleukin-mediated transcriptional regulation of pendrin and how this dysregulation impacts airway and esophagus epithelial homeostasis during inflammatory diseases.

Aims: Vitamin C plays a role in chemoprevention in cancer treatment, and Vitamin C modulates many regulators of inflammation in in vitro studies. The aim of this study is to assess the effect of Vitamin C supplementation with neoadjuvant chemoradiation in esophageal adenocarcinoma on the nuclear factor-kappa B (NF-κB) and associated cytokines., Materials and Methods: A total of 20 patients undergoing multimodal treatment for esophageal adenocarcinoma were randomized to receive Vitamin C (1000 mg/day) orally for 4 weeks or no supplementation. Pre- and post-Vitamin C endoscopic biopsies were used for the study of NF-κB activity and cytokine analysis., Results: NF-κB activity along with cytokines was activated in the cancer tissue pretreatment. Down-regulation in NF-κB activity was observed in 25% of cases, two from the Vitamin C arm posttreatment. There was a significant reduction in cytokines levels in the cancer group, and this effect was more pronounced in the Vitamin C group (P < 0.05)., Conclusions: Vitamin C supplementation had a mild protective effect in modulating of regulators of inflammation and carcinogenesis. Further studies with larger numbers of endpoints are needed to evaluate its effect on modulation of chemoradiation responses., Competing Interests: None

Background/aims: Esophageal mucosal damage often causes scar tissue, leading to refractory stricture. The aim of this study was to clarify the effect of hepatocyte growth factor (HGF) on esophageal mucosal repair and fibrosis leading to stricture in a rat model of esophageal ulcer., Methods: Esophageal ulcers were induced in rats by topical exposure of the lower esophageal serosa to acetic acid, followed by intraperitoneal administration of HGF (200 µg/day) using an osmotic pump for 7 days. The effect of HGF on esophageal mucosal injury was investigated macroscopically and microscopically. The effect of HGF on epithelial cell proliferation and the expression of genes closely associated with the development of fibrosis were also examined., Results: The administration of HGF for 7 days led to a significant reduction in the ulcerative area and enhanced the proliferation of esophageal epithelial cells. HGF treatment significantly decreased the fibrosis, and subsequently attenuated not only the foreshortening but also the narrowing of the esophagus. The expression levels of tissue inhibitor of metalloproteinase (TIMP)-1, -2, and matrix metalloproteinase (MMP)-2, -9 were significantly decreased among rats treated with HGF., Conclusion: HGF facilitates the repair of esophageal mucosal injury and may also ameliorate the esophageal fibrosis, possibly through enhanced re-epithelization., (© 2018 S. Karger AG, Basel.)

Background and Aim: Esophageal stricture is a serious adverse event secondary to extensive endoscopic submucosal dissection (ESD). The present study aimed to investigate the efficacy of carboxymethyl cellulose (CMC) sheets for the prevention of esophageal stricture after full circumferential ESD in an animal model., Methods: Fourteen porcine models were randomized into a control group (n = 7) and a CMC group (n = 7). Five-centimeter-long circumferential esophageal ESD was carried out at a distance of 40 to 45 cm from the incisors in all models. In the CMC group, CMC sheets were placed over the mucosal defect completely after ESD, whereas the control group underwent routine ESD only. Endoscopic examination was conducted after the first and second week post-ESD. Esophageal specimens were harvested during post-mortem and were evaluated for macroscopic and histological appearance. Blood serum levels of four pro-inflammatory or profibrotic cytokines were measured quantitatively., Results: The CMC group had better food tolerability during the second week post-ESD. The CMC group showed a significantly lower esophageal mucosal stricture rate compared to the control group. Histological assessments showed less fibrosis in the submucosal layer, milder damage to the muscularis propria, and enhanced re-epithelization in the CMC group. Serum transforming growth factor beta 1 levels were significantly lower in the CMC group post-ESD., Conclusion: Deployment of CMC sheets on the mucosal defect appears to be a promising method for preventing esophageal strictures after extensive ESD., (© 2018 Japan Gastroenterological Endoscopy Society.)

The oral cavity is frequently used to administer pharmaceutical drug products. This route of administration is seen as the most accessible for the majority of patients and supports an independent therapy management. For current oral dosage forms under development, the prediction of their unintended mucoadhesive properties and esophageal transit profiles would contribute for future administration safety, as concerns regarding unintended adhesion of solid oral dosage forms (SODF) during oro-esophageal transit still remain. Different in vitro methods that access mucoadhesion of polymers and pharmaceutical preparations have been proposed over the years. The same methods might be used to test non-adhesive systems and contribute for developing safe-to-swallow technologies. Previous works have already investigated the suitability of non-animal derived in vitro methods to assess such properties. The aim of this work was to review the in vitro methodology available in the scientific literature that used animal esophageal tissue to evaluate mucoadhesion and esophageal transit of pharmaceutical preparations. Furthermore, in vivo methodology is also discussed. Since none of the in vitro methods developed are able to mimic the complex swallowing process and oro-esophageal transit, in vivo studies in humans remain as the gold standard., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background/aims: The aim of this study was to investigate the effects of rebamipide on tight junction proteins in the esophageal mucosa in a rat model of gastroesophageal reflux disease (GERD)., Methods: GERD was created in rats by tying the proximal stomach. The rats were divided into a control group, a proton pump inhibitor (PPI) group, and a PPI plus rebamipide (PPI+R) group. Pantoprazole (5 mg/kg) was administered intraperitoneally to the PPI and PPI+R groups. An additional dose of rebamipide (100 mg/kg) was administered orally to the PPI+R group. Mucosal erosions, epithelial thickness, and leukocyte infiltration into the esophageal mucosa were measured in isolated esophagi 14 days after the procedure. A Western blot analysis was conducted to measure the expression of claudin-1, -3, and -4., Results: The mean surface area of mucosal erosions, epithelial thickness, and leukocyte infiltration were lower in the PPI group and the PPI+R group than in the control group. Western blot analysis revealed that the expression of claudin-3 and -4 was significantly higher in the PPI+R group than in the control group., Conclusions: Rebamipide may exert an additive effect in combination with PPI to modify the tight junction proteins of the esophageal mucosa in a rat model of GERD. This treatment might be associated with the relief of GERD symptoms.

Aim: To evaluate the anti-apoptotic effect of banhasasim-tang (BHSST) on chronic acid reflux esophagitis (CARE) using a rat model., Methods: A surgically-induced CARE model was established in Sprague-Dawley rats. The modeled rats were divided into a treatment group or untreated group, and given BHSST (1 g/kg body weight per day) or water, respectively, for 15 consecutive days ( n = 7 each group). Changes in expression of proteins related to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and apoptosis were assessed by western blotting. Changes in esophageal pathology were analyzed by gross and histological examinations., Results: The CARE exposure modeled rats showed increased levels of the NADPH oxidase subunit, NOX4 and p47 phox in the esophagus. The BHSST treatment completely resolved these CARE-related increases. The CARE rats also showed markers of cytokine stress, including elevated levels of TNF-α and reactive oxygen species as well as of the consequent increase in JNK activation, and subsequent decrease in pro-survival gene expression, such as of Bcl-2 . BHSST treatment resolved the CARE-related changes. BHSST also exerted an anti-apoptotic effect, as evidenced by altered expression of the apoptosis-related genes for bax, cytochrome c, and caspase 3. Finally, the BHSST treatment markedly ameliorated the CARE-related esophageal mucosal ulcerations., Conclusion: In the rat model of CARE, BHSST can suppress development of esophageal mucosal ulceration via regulation of reactive oxygen species-dependent apoptosis., Competing Interests: Conflict-of-interest statement: The authors declare no competing financial interests related to this study or its publication.

Gastroesophageal reflux disease (GERD) clinically predisposes to columnar Barrett's metaplasia (BM) in the distal esophagus. We demonstrate evidence supporting the cellular origin of BM from reprograming or transcommitment of resident normal esophageal squamous (NES) epithelial cells in response to acid and bile (A + B) exposure using an in vitro cell culture model. The hTERT-immortalized NES cell line NES-B10T was exposed 5 min/day to an A + B mixture for 30 wk. Morphological changes, mRNA, and protein expression levels for the inflammatory marker cyclooxygenase-2; the lineage-determining transcription factors TAp63 (squamous), CDX2, and SOX9 (both columnar); and the columnar lineage markers Villin, Muc-2, CK8, and mAb Das-1 (incomplete phenotype of intestinal metaplasia) were assessed every 10 wk. Markers of columnar lineage and inflammation increased progressively, while squamous lineage-determining transcriptional factors were significantly decreased both at the mRNA and/or protein level in the NES-B10T cells at/after A + B treatment for 30 wk. Distinct modifications in morphological features were only observed at/after 30 wk of A + B exposure. These changes acquired by the NES-B10T 30-wk cells were retained even after cessation of A + B exposure for at least 3 wk. This study provides evidence that chronic exposure to the physiological components of gastric refluxate leads to repression of the discernable squamous transcriptional factors and activation of latent columnar transcriptional factors. This reflects the alteration in lineage commitment of the precursor-like biphenotypic, NES-B10T cells in response to A + B exposure as the possible origin of BM from the resident NES cells. NEW & NOTEWORTHY This study provides evidence of the origins of Barrett's metaplasia from lineage transcommitment of resident esophageal cells after chronic exposure to gastroesophageal refluxate. The preterminal progenitor-like squamous cells alter their differentiation and develop biphenotypic characteristics, expressing markers of incomplete-type columnar metaplasia. Development of these biphenotypic precursors in vitro is a unique model to study pathogenesis of Barrett's metaplasia and esophageal adenocarcinoma.

Significant stress softening recovery after potassium chloride (KCl) administration was previously demonstrated in the intact rat esophageal wall. The aim of this study is to investigate the effect of KCl activation on stress softening recovery in the separated mucosa-submucosa layer and muscle layer of rat esophagus. Three series of loading-unloading distensions were carried out on 10 rat esophagi where the two separated layers were distended at luminal pressure levels 0.5, 1.0 and 2.0 kPa. Numerous distension cycles were done in [Formula: see text]-free Krebs solution before and after activation with KCl (110 mmol) for 3 min in calcium-containing media. The diameter and luminal pressure were recorded for stress and strain calculation. During KCl activation, the muscle layer responded with a high-amplitude contraction, and the mucosa-submucosa layer responded with a longer-lasting low-amplitude contraction. The hysteresis loop areas from the muscle layer were significantly bigger than those from the mucosa-submucosa layer at distension pressures 1.0 and 2.0 kPa ([Formula: see text]). The calculated stiffness in the mucosa-submucosa layer was significantly higher than that in the muscle layer ([Formula: see text]). After activation with KCl, the stored energy and the stiffness after the stress and viscoelasticity softening increased in both layers, indicating that the reversible stress softening in esophagus after KCl activation is existed in both layers.

Nonerosive reflux disease (NERD) is a highly prevalent phenotype of the gastroesophageal reflux disease. In this study, we developed a novel murine model of NERD in mice with microscopic inflammation and impairment in the epithelial esophageal barrier. Female Swiss mice were subjected to the following surgical procedure: the transitional region between the forestomach and the glandular portion of the stomach was ligated, and a nontoxic ring was placed around the duodenum near the pylorus. The control group underwent sham surgery. The animals were euthanized at 1, 3, 7, and 14 days after surgery. Survival and body weight were monitored daily. Esophageal wet weight, macroscopic lesion, histopathological alterations, myeloperoxidase (MPO) activity, cytokine levels, transepithelial electrical resistance (TEER), and mucosal permeability were evaluated. The survival rate was 78% at 14 days, with mild loss in body weight. Surgery did not induce erosive esophagitis but instead induced microscopic inflammation and increased esophageal wet weight, IL-6, keratinocyte-derived cytokine (KC) levels, and MPO activity with maximal peak between 3 and 7 days and resolution at 14 days postsurgery. Epithelial esophageal barrier was evaluated in operated mice at 7 and 14 days postsurgery; a decrease in TEER and increase in the esophageal epithelial permeability were observed compared with the sham-operated group. In addition, the inhibition of acid secretion with omeprazole significantly prevented the esophageal inflammation and impairment of barrier function at 7 days postsurgery. Thus we established a novel experimental model of NERD in mice, which can contribute to understanding the pathophysiological events associated with NERD. NEW & NOTEWORTHY In this study, we standardized an experimental model of nonerosive reflux disease (NERD) in mice. This model involves an acute inflammatory response followed by impaired esophageal mucosal integrity, even in the absence of inflammation. Thus this model can serve for evaluation of pathophysiological aspects of NERD and open new perspectives for therapeutic strategies for patients with this disorder., (Copyright © 2017 the American Physiological Society.)

In recent years, proton pump inhibitors (PPIs) have come under great scrutiny due to possible adverse, long-term side effects. At the same time, Barrett's esophagus, a premalignant condition in the esophagus, continues to be a disease whose course is thought to be improved by the use of PPIs. We review the impact of proton pump therapy on the esophagus and on Barrett's mucosa. In analyzing changes on a cellular level, we explore the effect of mixed gastric refluxate and the complex cascade that ensues with esophageal exposure of these contents. Because the incidence of esophageal adenocarcinoma is on the rise, we explore other factors that may contribute to the progression of Barrett's from non-dysplastic mucosa to esophageal adenocarcinoma. By revisiting the need for adequate acid suppression in Barrett's and increasing our understanding of other possible factors that may have an effect of Barrett's progression, we hope to support our multifaceted approach to acid suppression in patients with Barrett's esophagus., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The present study was conducted to evaluate both antioxidant and anti-inflammatory activity of Banhasasim-tang (BHSST) on chronic acid reflux esophagitis (CRE) model. Rat CRE model was established operatively and then treated with BHSST (1 g/kg body weight per day) for 15 days Esophageal pathological changes were analyzed using macroscopic examination and hematoxylin/eosin staining. The antioxidant and inflammatory protein levels were determined using Western blotting. The administration of BHSST significantly reduced both the overexpression of serum reactive oxygen species (ROS) and an excessive formation of thiobarbituric acid-reactive substances (TBARS) in esophagus tissue. Thus, the severity of esophageal ulcer was lower in BHSST treated rats than control rats on the gross and histological evaluation. Nuclear factor-erythroid 2-related factor 2 (Nrf2) led to the upregulation of antioxidant enzyme including SOD, GPx-1/2, and HO-1 by binding to antioxidant response element (ARE). Moreover, BHSST administration markedly reduced the expression of inflammatory proteins through mitogen-activated protein kinase- (MAPK-) related signaling pathways and decreased significantly the protein expressions of inflammatory mediators and cytokines by inhibition of nuclear factor-kappa B (NF- κ B) activation. Taken together, these results support the fact that BHSST administration can suppress the development of esophageal mucosal ulcer via regulating inflammation through the activation of the antioxidant pathway., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Background/aim: The effects of vonoprazan and proton pump inhibitors (PPIs) in patients with reflux esophagitis (RE) have not yet been compared using multichannel intraluminal impedance-pH (MII-pH)., Methods: A total of 8 patients with persistent gastric mucosal injury, despite completing an 8-week standard PPI therapy, were enrolled in the study. While they were on standard PPI therapy, the baseline values of reflux parameters, holding time ratio (HTR) of gastric pH >4, and esophageal pH <4 were obtained by using 24 h MII-pH monitoring. They were re-evaluated after discontinuation of the therapy and 4 weeks of subsequent treatment with vonoprazan 20 mg/day., Results: The patients were found to be CYP2C19 extensive metabolizers and negative for Helicobacter pylori infection. In 7 patients (87.5%), the mucosal lesions had healed completely after vonoprazan therapy. A significant increase in gastric pH >4 HTR was observed, from 26.5 to 78.0% (p = 0.029). A reduction in esophageal pH <4 HTR was also observed but it was not statistically significant. Furthermore, acid clearance time and the total number of reflux events, including acid and proximal reflux events, were significantly reduced., Conclusion: Vonoprazan may be a better therapy for the treatment of patients with PPI-refractory RE., (© 2017 S. Karger AG, Basel.)

Background: Vonoprazan (VPZ) is a novel potassium-competitive acid blocker that may be clinically beneficial for proton pump inhibitor (PPI)-resistant reflux esophagitis (RE). The aim of this study was to investigate the efficacies of VPZ therapy at 20 mg for 4 weeks in patients with PPI-resistant RE and VPZ maintenance therapy at 10 mg for 8 weeks in patients who have been successfully treated., Methods: Subjects comprised 24 patients with PPI-resistant RE (Los Angeles classification grade A/B/C/D: 3/7/11/3). After confirming PPI-resistant RE by endoscopy, 20 mg VPZ was administered. Endoscopy was performed 4 weeks after the initiation of VPZ. Symptoms were evaluated using the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG). Maintenance therapy with 10 mg VPZ was performed and endoscopy was conducted after 8 weeks., Results: In 21 (87.5%) out of 24 patients, esophageal mucosal breaks were successfully treated by 20 mg VPZ. The median FSSG score was significantly lower on days 1-7, 14, and 28 after the initiation of VPZ than before its administration. Maintenance therapy with 10 mg VPZ prevented the relapse of esophageal mucosal breaks in 16 (76.2%) out of 21 patients., Conclusion: VPZ was effective for most patients with PPI-resistant RE., (© 2017 S. Karger AG, Basel.)

Background and Aims: Gastroesophageal reflux disease (GERD) therapy is challenging and suppression of acid secretion or prokinetics do not cure all cases. Some drugs with protective action on the esophageal mucosa have been used alternatively or in association with proton pump inhibitors (PPIs) and/or prokinetics. The Romanian Society of Neurogastroenterology undertook an Evidence-Based analysis, from which this position paper evolved., Methods: We performed a systematic literature search in PubMed until October 2015, using the terms: sucralfate, guaiazulene, gaiazulene, dimethicone, alginate, antacids and gastroesophageal reflux. Forty-seven papers were included and analyzed. Several statements were elaborated regarding the use of these drugs in GERD. The evidence and recommendations were discussed between the authors., Results: There is evidence in the medical literature suggesting the benefit of these drugs in GERD. In patients with persistent or mild reflux symptoms antacids rapidly relieve heartburn. Alginate-antacid combination is superior both over placebo and antacids to treat mild reflux symptoms, and can be used to treat persistent reflux symptoms despite acid suppressant therapy. Sucralfate is superior over placebo in alleviating GERD symptoms and can be used as maintenance therapy. Guaiazulene-dimethicone improves the quality of life in patients with GERD., Conclusions: Drugs used to protect the esophageal mucosa against acid are useful in alleviating chronic heartburn, especially in patients with mild reflux symptoms.

Background: Serotonin regulates gastrointestinal function, and mast cells are a potential nonneuronal source of serotonin in the esophagus. Tight junction (TJ) proteins in the esophageal epithelium contribute to the barrier function, and the serotonin signaling pathway may contribute to epithelial leakage in gastroesophageal reflux disease. Therefore, the aim of this study was to investigate the role of serotonin on barrier function, TJ proteins, and related signaling pathways., Methods: Normal primary human esophageal epithelial cells were cultured with use of an air-liquid interface system. Serotonin was added to the basolateral compartment, and transepithelial electrical resistance (TEER) was measured. The expression of TJ proteins and serotonin receptor 7 (5-HT 7 ) was assessed by Western blotting. The involvement of 5-HT 7 was assessed with use of an antagonist and an agonist. The underlying cellular signaling pathways were examined with use of specific blockers., Results: Serotonin decreased TEER and reduced the expression of TJ proteins ZO-1, occludin, and claudin 1, but not claudin 4. A 5-HT 7 antagonist blocked the serotonin-induced decrease in TEER, and a 5-HT 7 agonist decreased TEER. Inhibition of p38 mitogen-activated protein kinase (MAPK) reduced the serotonin-induced decrease in TEER. Inhibition of p38 MAPK blocked the decrease of ZO-1 levels, whereas extracellular-signal-regulated kinase (ERK) inhibition blocked the decrease in occludin levels. Cell signaling pathway inhibitors had no effect on serotonin-induced alterations in claudin 1 and claudin 4 levels. Serotonin induced phosphorylation of p38 MAPK and ERK, and a 5-HT 7 antagonist partially blocked serotonin-induced phosphorylation of p38 MAPK but not that of ERK., Conclusions: Serotonin disrupted esophageal squamous epithelial barrier function by modulating the levels of TJ proteins. Serotonin signaling pathways may mediate the pathogenesis of gastroesophageal reflux disease.