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1
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Hossa K, Małecka-Wojciesko E. Advances in Gastroesophageal Reflux Disease Management: Exploring the Role of Potassium-Competitive Acid Blockers and Novel Therapies. Pharmaceuticals (Basel) 2025; 18:699. [PMID: 40430518 PMCID: PMC12115254 DOI: 10.3390/ph18050699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/29/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
Gastroesophageal reflux disease (GERD) is a prevalent chronic gastrointestinal disorder that affects a substantial proportion of the global population. It is characterized by the extensive backward flow of stomach contents into the esophagus, leading to troublesome symptoms and potential complications. Proton pump inhibitors (PPIs) have long been the cornerstone of pharmacological treatment for GERD, effectively suppressing gastric acid secretion. However, a substantial subset of patients, referred to as PPI-refractory GERD, experience inadequate symptom control despite optimal PPI therapy. GERD significantly impacts patients' quality of life, affecting domains, such as vitality, pain, and physical functioning. Consequently, there is an urgent need for alternative therapeutic strategies and novel pharmacologic agents to provide more effective, long-term relief. Emerging treatment options include potassium-competitive acid blockers (PCABs) like vonoprazan, which offer more potent and sustained inhibition of gastric acid secretion compared to traditional PPIs. Additionally, prokinetic agents such as itopride have gained attention due to their potential to improve GERD symptoms by enhancing gastrointestinal motility and accelerating gastric emptying. This article reviews the mechanisms of action, clinical efficacy, and potential of these novel therapeutic approaches in improving patient outcomes in GERD management. With the growing prevalence of PPI resistance and side effects, a personalized, multifaceted approach to treatment is becoming increasingly necessary to optimize care for patients with GERD.
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Affiliation(s)
| | - Ewa Małecka-Wojciesko
- Department of Digestive Tract Diseases, Medical University of Lodz, 90-419 Lodz, Poland;
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2
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Guo Z, Tang Y, Li M, Yang L, Liu L, Li P, Liu S. Integrated transcriptomic and metabolomic analyses reveal the mechanism by which quercetin inhibits reflux esophagitis in rats. PLoS One 2025; 20:e0321959. [PMID: 40327723 PMCID: PMC12054900 DOI: 10.1371/journal.pone.0321959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Accepted: 03/06/2025] [Indexed: 05/08/2025] Open
Abstract
Quercetin relieved symptoms in rats with reflux esophagitis (RE), but the underlying mechanism remains unclear. Quercetin attenuated esophageal mucosal inflammation in RE rats by inhibiting the production of the inflammatory factors interleukin-1β (IL-1β) and interleukin-6 (IL-6). Additionally, through transcriptomic and metabolomic analysis, we found that metabolites related to bile acid metabolism, such as taurine, taurocholic acid, and nicotinamide, were closely associated with RE in rats. Quercetin reduced the expression of bile acid-related genes such as Cd38, seizure related 6 homolog like 2 (Sez6l2), and nitric oxide synthase 2 (Nos2), which may be characteristic genes and therapeutic targets for RE.
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Affiliation(s)
- Zheng Guo
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yanping Tang
- Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin, China
| | - Mingli Li
- Graduate School, Tianjin Medical University, Tianjin, China
| | - Lei Yang
- Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin, China
| | - Lei Liu
- Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin, China
| | - Peicai Li
- Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin, China
| | - Siyu Liu
- Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin, China
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3
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Paulrasu K, Caspa Gokulan R, El-Rifai W, Chen Z, Que J, Wang TC, Boutaud OG, Briegel K, Dikalov SI, Garcia-Buitrago MT, Zaika AI. Chronic Gastroesophageal Reflux Dysregulates Proteostasis in Esophageal Epithelial Cells. Cell Mol Gastroenterol Hepatol 2024; 19:101434. [PMID: 39637942 PMCID: PMC11786911 DOI: 10.1016/j.jcmgh.2024.101434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 11/25/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND & AIMS Gastroesophageal reflux disease (GERD) is a common digestive disorder that is characterized by esophageal tissue damage produced by exposure of the esophageal lining to the gastric refluxate. GERD can raise the risk of multiple serious complications including esophageal tumors. At the molecular levels, GERD-affected tissues are characterized by strong oxidative stress and the formation of reactive isolevuglandins (isoLGs). These products of lipid peroxidation rapidly interact with cellular proteins forming protein adducts. Here, we investigated the interrelationship between isoLG adduction and aggregation of cellular proteins. METHODS Protein misfolding and aggregation were analyzed using multiple protein misfolding and aggregation assays. Pathologic consequences of protein adduction and aggregation were studied using human and murine esophageal tissues. Surgical model of esophageal reflux injury and L2-IL1β transgenic mice were used to investigate the mechanisms of protein misfolding and aggregation. RESULTS Our studies demonstrate that gastroesophageal reflux causes protein misfolding and aggregation that is associated with severity of GERD. Dysregulation of proteostasis induces ferroptotic cell death and is mediated by modification of cellular proteins with reactive isoLGs that can be prevented by isoLG scavengers. CONCLUSIONS GERD causes dysregulation of cellular proteostasis, accumulation of isoLG protein adducts, misfolded, and aggregated proteins that promote ferroptotic cell death. Taken together, this study suggests that GERD has similarities to other known pathologic conditions that are characterized by protein misfolding and aggregation.
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Affiliation(s)
| | - Ravindran Caspa Gokulan
- Department of Surgery, University of Miami, Miami, Florida; Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Wael El-Rifai
- Department of Surgery, University of Miami, Miami, Florida
| | - Zhibin Chen
- Department of Microbiology and Immunology, University of Miami, Miami, Florida
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, New York
| | - Timothy C Wang
- Department of Medicine, Columbia University Medical Center, New York, New York
| | - Olivier G Boutaud
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
| | | | - Sergey I Dikalov
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | - Alexander I Zaika
- Department of Surgery, University of Miami, Miami, Florida; Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida; Department of Veterans Affairs, Miami VA Healthcare System, Miami, Florida.
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4
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Blignaut CJ, Kadwa AR, Basson EP, Zeiler GE. Comparing methods for detection of gastro-oesophageal reflux in anaesthetized dogs. Vet Anaesth Analg 2024; 51:629-640. [PMID: 39256095 DOI: 10.1016/j.vaa.2024.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 07/03/2024] [Accepted: 08/02/2024] [Indexed: 09/12/2024]
Abstract
OBJECTIVE To compare the sensitivity and specificity of pH with multichannel intraluminal impedance (pH-MII), pH-metry (pH) alone and MII alone to direct observation of GOR by endoscopy in anaesthetized dogs. STUDY DESIGN A prospective comparative trial in a live canine model. ANIMALS A group of 35 (22 females, 13 males) dogs of various breeds. The mean (range) body weight and age were 31.9 (14-40) kg and 5.6 (0.75-12) years, respectively. METHODS All dogs were premedicated with medetomidine and morphine, anaesthesia was induced with propofol and maintained on isoflurane in oxygen. A monitoring assembly consisting of an endoscopy camera, endotracheal tube and a disposable flexible pH-MII catheter was used to measure oesophageal pH, MII and directly visualize reflux. Visual reflux score was (0-3) and pH was recorded on a data capture sheet. Reflux was considered to have occurred whenever oesophageal pH was < 4.0 or > 7.5, device software analysing MII data detected fluid or a visual reflux score of 2 or 3 were assigned. Receiver operator curves (ROC) analysis was used to determine sensitivity and specificity for each monitoring method to detect GOR. RESULTS Endoscopy identified GOR in 20 dogs (57%), pH-MII in 19 dogs (54%), pH alone in 13 dogs (37%) and MII alone in 12 dogs (24%). ROC analysis showed fair accuracy for pH-MII and pH alone, whereas MII demonstrated low accuracy. CONCLUSIONS AND CLINICAL RELEVANCE In conclusion, pH-MII is a reliable method for detecting GOR and emerges as a promising tool for future research. Endoscopy is reliable and provides the ability to subjectively quantify the volume of reflux; however, it lacks the ability to discern the pH of refluxate. pH alone misses reflux events with intermediate pH (4.1-7.4). Incorporation of impedance addresses some of the limitations associated with pH alone and enhances diagnostic accuracy.
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Affiliation(s)
- Christiaan J Blignaut
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, South Africa.
| | - Abdur R Kadwa
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, South Africa; Anaesthesia Services, Bryanston Veterinary Hospital, Bryanston, Johannesburg, South Africa
| | - Etienne P Basson
- Anaesthesia and Critical Care Services, Valley Farm Animal Hospital, Faerie Glen, Pretoria, South Africa
| | - Gareth E Zeiler
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, South Africa; Anaesthesia and Critical Care Services, Valley Farm Animal Hospital, Faerie Glen, Pretoria, South Africa
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5
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Iijima K. Etiologic factors for Barrett's esophagus: toward countermeasures in Asia. Expert Rev Gastroenterol Hepatol 2024; 18:407-420. [PMID: 39072626 DOI: 10.1080/17474124.2024.2386367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 07/26/2024] [Indexed: 07/30/2024]
Abstract
INTRODUCTION Over the past several decades, Europe and the United States have experienced a rapid increase in esophageal adenocarcinoma. Research and countermeasures against Barrett's esophagus, its precancerous lesion, are progressing. Because esophageal adenocarcinoma has an extremely poor prognosis when diagnosed in an advanced stage, recommendations for early cancer detection have been made based on the various proven etiological factors of Barrett's esophagus and the actual cancer risk of Barrett's esophagus. In recent years, there have been indications of an increase in esophageal adenocarcinoma in Japan, and a similar trend of cancer will occur shortly in other Asian countries. Consequently, Asian countries must implement similar countermeasures against Barrett's esophagus and esophageal adenocarcinoma, referencing the knowledge gained thus far in Europe and the United States. AREAS COVERED This review summarizes the latest findings on the etiologic factors of Barrett's esophagus and discusses the differences between Westerners and Asians. The current status of Barrett's esophagus in Japan and other Asian countries is also summarized. EXPERT OPINION The etiological factors and cancer incidence of Barrett's esophagus in Asia diverge somewhat from those observed in Europe and America. Therefore, it is imperative to implement measures that are tailored to the actual circumstances of Asian people.
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Affiliation(s)
- Katsunori Iijima
- Department of Gastroenterology, Akita University Graduate School of Medicine, Akita, Japan
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Wada M, Minoda Y, Ihara E, Tsuru H, Hata Y, Nagatomo S, Esaki M, Bai X, Tanaka Y, Chinen T, Ogino H, Ogawa Y. Development of a new endoscopy system to visualize bilirubin for the diagnosis of duodenogastroesophageal reflux. Dig Endosc 2024; 36:904-914. [PMID: 38130063 DOI: 10.1111/den.14749] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 12/19/2023] [Indexed: 12/23/2023]
Abstract
OBJECTIVES Reflux hypersensitivity (RH) is a form of refractory gastroesophageal reflux disease in which duodenogastroesophageal reflux (DGER) plays a role. This study aimed to determine the usefulness of an endoscopy system equipped with image-enhanced technology for evaluating DGER and RH. METHODS The image enhancement mode for detecting bilirubin and calculated values were defined as the Bil mode and Bil value, respectively. First, the visibility of the Bil mode was validated for a bilirubin solution and bile concentrations ranging from 0.01% to 100% (0.002-20 mg/dL). Second, visibility scores of the Bil mode, when applied to the porcine esophagus sprayed with a bilirubin solution, were compared to those of the blue laser imaging (BLI) and white light imaging (WLI) modes. Third, a clinical study was conducted to determine the correlations between esophageal Bil values and the number of nonacid reflux events (NNRE) during multichannel intraluminal impedance-pH monitoring as well as the utility of esophageal Bil values for the differential diagnosis of RH. RESULTS Bilirubin solution and bile concentrations higher than 1% were visualized in red using the Bil mode. The visibility score was significantly higher with the Bil mode than with the BLI and WLI modes for 1% to 6% bilirubin solutions (P < 0.05). The esophageal Bil value and NNRE were significantly positively correlated (P = 0.031). The area under the receiver operating characteristic curve for the differential diagnosis of RH was 0.817. CONCLUSION The Bil mode can detect bilirubin with high accuracy and could be used to evaluate DGER in clinical practice.
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Affiliation(s)
- Masafumi Wada
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yosuke Minoda
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eikichi Ihara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hirotaka Tsuru
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshitaka Hata
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shuzaburo Nagatomo
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mitsuru Esaki
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Xiaopeng Bai
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshimasa Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takatoshi Chinen
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Haruei Ogino
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Oleszycka E, O’Brien EC, Freeley M, Lavelle EC, Long A. Bile acids induce IL-1α and drive NLRP3 inflammasome-independent production of IL-1β in murine dendritic cells. Front Immunol 2023; 14:1285357. [PMID: 38090554 PMCID: PMC10711081 DOI: 10.3389/fimmu.2023.1285357] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/01/2023] [Indexed: 12/18/2023] Open
Abstract
Bile acids are amphipathic molecules that are synthesized from cholesterol in the liver and facilitate intestinal absorption of lipids and nutrients. They are released into the small intestine upon ingestion of a meal where intestinal bacteria can modify primary into secondary bile acids. Bile acids are cytotoxic at high concentrations and have been associated with inflammatory diseases such as liver inflammation and Barrett's Oesophagus. Although bile acids induce pro-inflammatory signalling, their role in inducing innate immune cytokines and inflammation has not been fully explored to date. Here we demonstrate that the bile acids, deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) induce IL-1α and IL-1β secretion in vitro in primed bone marrow derived dendritic cells (BMDCs). The secretion of IL-1β was found not to require expression of NLRP3, ASC or caspase-1 activity; we can't rule out all inflammasomes. Furthermore, DCA and CDCA were shown to induce the recruitment of neutrophils and monocytes to the site of injection an intraperitoneal model of inflammation. This study further underlines a mechanistic role for bile acids in the pathogenesis of inflammatory diseases through stimulating the production of pro-inflammatory cytokines and recruitment of innate immune cells.
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Affiliation(s)
- Ewa Oleszycka
- Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Eoin C. O’Brien
- Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Michael Freeley
- School of Biotechnology, Dublin City University, Dublin, Ireland
| | - Ed C. Lavelle
- Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Aideen Long
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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8
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Jodorkovsky D, Katzka DA, Gyawali CP. A perspective on the clinical relevance of weak or nonacid reflux. Neurogastroenterol Motil 2023; 35:e14671. [PMID: 37702263 DOI: 10.1111/nmo.14671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/04/2023] [Accepted: 08/21/2023] [Indexed: 09/14/2023]
Abstract
BACKGROUND Advances in ambulatory esophageal reflux monitoring that incorporated impedance electrodes to pH catheters have resulted in better characterization of retrograde bolus flow in the esophagus. With pH-impedance monitoring, in addition to acid reflux episodes identified by pH drops below 4.0, weakly acid reflux (WAR, pH 4-7) and nonacid reflux (NAR, pH >7.0) are also recognized, although both may be included under the umbrella term NAR. However, despite identification of ambulatory pH-impedance monitoring, data on clinical relevance and prognostic value of NAR are limited. The Lyon Consensus, an international expert review that defines conclusive metrics for gastroesophageal reflux disease (GERD), identifies NAR as "supportive" but not conclusive for GERD. PURPOSE This review provides perspectives on whether NAR fulfills three criteria for clinical relevance: whether NAR sufficiently explains pathogenesis of symptoms, whether it is associated with meaningful manifestations of GERD, and whether it can predict treatment efficacy.
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Affiliation(s)
- Daniela Jodorkovsky
- Division of Gastroenterology, Mount Sinai West & Morningside, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - David A Katzka
- Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, New York, USA
| | - C Prakash Gyawali
- Division of Gastroenterology, Washington University in St. Louis, St. Louis, Missouri, USA
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9
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Bernard JN, Chinnaiyan V, Almeda J, Catala-Valentin A, Andl CD. Lactobacillus sp. Facilitate the Repair of DNA Damage Caused by Bile-Induced Reactive Oxygen Species in Experimental Models of Gastroesophageal Reflux Disease. Antioxidants (Basel) 2023; 12:1314. [PMID: 37507854 PMCID: PMC10376144 DOI: 10.3390/antiox12071314] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/16/2023] [Accepted: 06/19/2023] [Indexed: 07/30/2023] Open
Abstract
Gastroesophageal reflux disease (GERD) leads to the accumulation of bile-induced reactive oxygen species and oxidative stress in esophageal tissues, causing inflammation and DNA damage. The progression sequence from healthy esophagus to GERD and eventually cancer is associated with a microbiome shift. Lactobacillus species are commensal organisms known for their probiotic and antioxidant characteristics in the healthy esophagus. This prompted us to investigate how Lactobacilli survive in a bile-rich environment during GERD, and to identify their interaction with the bile-injured esophageal cells. To model human reflux conditions, we exposed three Lactobacillus species (L. acidophilus, L. plantarum, and L. fermentum) to bile. All species were tolerant to bile possibly enabling them to colonize the esophageal epithelium under GERD conditions. Next, we assessed the antioxidant potential of Lactobacilli and role in bile injury repair: we measured bile-induced DNA damage using the ROS marker 8-oxo guanine and COMET assay. Lactobacillus addition after bile injury accelerated repair of bile-induced DNA damage through recruitment of pH2AX/RAD51 and reduced NFκB-associated inflammation in esophageal cells. This study demonstrated anti-genotoxic and anti-inflammatory effects of Lactobacilli, making them of significant interest in the prevention of Barrett's esophagus and esophageal adenocarcinoma in patients with GERD.
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Affiliation(s)
- Joshua N Bernard
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - Vikram Chinnaiyan
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - Jasmine Almeda
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - Alma Catala-Valentin
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - Claudia D Andl
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
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10
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de Waal T, Brouwers J, Berben P, Flanagan T, Tack J, Vandenberghe W, Vanuytsel T, Augustijns P. Characterization of Aspirated Duodenal Fluids from Parkinson's Disease Patients. Pharmaceutics 2023; 15:pharmaceutics15041243. [PMID: 37111729 PMCID: PMC10145225 DOI: 10.3390/pharmaceutics15041243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/16/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023] Open
Abstract
Parkinson's disease, one of the most common neurodegenerative diseases, may not only affect the motor system, but also the physiology of the gastrointestinal tract. Delayed gastric emptying, impaired motility and altered intestinal bacteria are well-established consequences of the disease, which can have a pronounced effect on the absorption of orally administered drugs. In contrast, no studies have been performed into the composition of intestinal fluids. It is not unlikely that Parkinson's disease also affects the composition of intestinal fluids, a critical factor in the in vitro and in silico simulation of drug dissolution, solubilization and absorption. In the current study, duodenal fluids were aspirated from Parkinson's disease (PD) patients and age-matched healthy controls (healthy controls, HC) consecutively in fasted and fed conditions. The fluids were then characterized for pH, buffer capacity, osmolality, total protein, phospholipids, bile salts, cholesterol and lipids. In a fasted state, the intestinal fluid composition was highly similar in PD patients and healthy controls. In general, the same was true for fed-state fluids, apart from a slightly slower and less pronounced initial change in factors directly affected by the meal (i.e., buffer capacity, osmolality, total protein and lipids) in PD patients. The absence of a fast initial increase for these factors immediately after meal intake, as was observed in healthy controls, might result from slower gastric emptying in PD patients. Irrespective of the prandial state, a higher relative amount of secondary bile salts was observed in PD patients, potentially indicating altered intestinal bacterial metabolism. Overall, the data from this study indicate that only minor disease-specific adjustments in small intestinal fluid composition should be considered when simulating intestinal drug absorption in PD patients.
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Affiliation(s)
- Tom de Waal
- Drug Delivery and Disposition, KU Leuven, 3000 Leuven, Belgium
| | | | - Philippe Berben
- Pharmaceutical Sciences, UCB Pharma SA, 1420 Braine-l'Alleud, Belgium
| | - Talia Flanagan
- Pharmaceutical Sciences, UCB Pharma SA, 1420 Braine-l'Alleud, Belgium
| | - Jan Tack
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, 3000 Leuven, Belgium
- Translational Research Center for Gastrointestinal Disorders, TARGID, KU Leuven, 3000 Leuven, Belgium
| | - Wim Vandenberghe
- Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Tim Vanuytsel
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, 3000 Leuven, Belgium
- Translational Research Center for Gastrointestinal Disorders, TARGID, KU Leuven, 3000 Leuven, Belgium
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11
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Caspa Gokulan R, Paulrasu K, Azfar J, El-Rifai W, Que J, Boutaud OG, Ban Y, Gao Z, Buitrago MG, Dikalov SI, Zaika AI. Protein adduction causes non-mutational inhibition of p53 tumor suppressor. Cell Rep 2023; 42:112024. [PMID: 36848235 PMCID: PMC9989503 DOI: 10.1016/j.celrep.2023.112024] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/04/2022] [Accepted: 01/09/2023] [Indexed: 01/24/2023] Open
Abstract
p53 is a key tumor suppressor that is frequently mutated in human tumors. In this study, we investigated how p53 is regulated in precancerous lesions prior to mutations in the p53 gene. Analyzing esophageal cells in conditions of genotoxic stress that promotes development of esophageal adenocarcinoma, we find that p53 protein is adducted with reactive isolevuglandins (isoLGs), products of lipid peroxidation. Modification of p53 protein with isoLGs diminishes its acetylation and binding to the promoters of p53 target genes causing modulation of p53-dependent transcription. It also leads to accumulation of adducted p53 protein in intracellular amyloid-like aggregates that can be inhibited by isoLG scavenger 2-HOBA in vitro and in vivo. Taken together, our studies reveal a posttranslational modification of p53 protein that causes molecular aggregation of p53 protein and its non-mutational inactivation in conditions of DNA damage that may play an important role in human tumorigenesis.
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Affiliation(s)
| | | | - Jamal Azfar
- Department of Surgery, University of Miami, Miami, FL, USA
| | - Wael El-Rifai
- Department of Surgery, University of Miami, Miami, FL, USA
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - Olivier G Boutaud
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yuguang Ban
- Department of Public Health Sciences, University of Miami, Miami, FL, USA
| | - Zhen Gao
- Department of Public Health Sciences, University of Miami, Miami, FL, USA
| | | | - Sergey I Dikalov
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alexander I Zaika
- Department of Surgery, University of Miami, Miami, FL, USA; Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL, USA.
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12
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Li HS, Chu CL. Intestinal metaplasia in progression of Barrett's esophagus to esophageal adenocarcinoma. Shijie Huaren Xiaohua Zazhi 2023; 31:41-47. [DOI: 10.11569/wcjd.v31.i2.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
The incidence of esophageal adenocarcinoma (EAC) has been increasing year by year. The prognosis of EAC is poor, and the 5-year survival rate is less than 20%. Barrett's esophagus (BE) is the only known precancerous lesion of EAC. BE with intestinal metaplasia (IM) has a higher risk of progressing to EAC. Exploring the mechanism of IM and finding targeted therapeutic targets for BE has become an important measure for tumor prevention. Bile acid reflux is considered an important factor in the occurrence of IM and promotes the progression of BE to EAC. However, the molecular regulatory mechanism of bile reflux induced IM and carcinogenesis remains unclear. This article reviews the environment, significance, and cell origin theory of IM, toxic effects of bile reflux, and molecular changes of IM progression to tumor, aiming to improve clinicians' understanding of IM in BE and provide evidence for early intervention of BE and prevention and treatment of EAC.
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Affiliation(s)
- Hai-Su Li
- Jinan Central Hospital, Jinan Key Translational Gastroenterology Laboratory, Jinan Digestive Diseases Clinical Research Center, Jinan 250013, Shandong Province, China
| | - Chuan-Lian Chu
- Jinan Central Hospital, Jinan Key Translational Gastroenterology Laboratory, Jinan Digestive Diseases Clinical Research Center, Jinan 250013, Shandong Province, China
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13
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Abe I, Suzuki K, Kimura Y, Tamaki S, Endo Y, Ichida K, Muto Y, Watanabe F, Saito M, Konishi F, Rikiyama T. Enhancement of DNA hypomethylation alterations by gastric and bile acids promotes chromosomal instability in Barrett's epithelial cell line. Sci Rep 2022; 12:20710. [PMID: 36456615 PMCID: PMC9715700 DOI: 10.1038/s41598-022-25279-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022] Open
Abstract
Gastric and bile acid reflux leads to chronic inflammation, resulting in methylation alterations in Barrett's esophagus (BE) together with chromosomal instability (CIN). We investigated DNA hypomethylation following acid exposure and confirmed its significance in BE-related carcinogenesis by inducing CIN in vitro. OACP4C, an esophageal cancer cell line, and CP-A, a non-dysplastic cell line originating from BE, were exposed to acidic conditions using deoxycholic acid. CP-A exhibited substantially increased DNA hypomethylation of alpha satellite sequences in the centromere region, as well as increased levels of alpha satellite transcripts, but no changes were observed in the long interspersed nucleotide element-1 sequences distributed throughout the entire genome. These changes were not clearly found in OACP4C. Copy number changes at specific chromosomes were identified in CP-A, along with an increased number of cells exhibiting abnormal segregations, whereas these changes were rarely observed in OACP4C. The changes were maintained after several cell divisions. These findings suggest that alpha satellites are likely targets of DNA hypomethylation induced by acid exposure. CP-A was more sensitive to acid exposure than OACP4C, indicating that acid-induced DNA hypomethylation is involved in cancer development rather than progression, which could be involved in the underlying mechanism of esophagogastric junction carcinoma development.
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Affiliation(s)
- Iku Abe
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Koichi Suzuki
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Yasuaki Kimura
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Sawako Tamaki
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Yuhei Endo
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Kosuke Ichida
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Yuta Muto
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Fumiaki Watanabe
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Masaaki Saito
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Fumio Konishi
- Department of Surgery, Nerima-Hikarigaoka Hospital, 2-5-1, Hikarigaoka, Nerima-ku, Tokyo, 179-0072 Japan
| | - Toshiki Rikiyama
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
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14
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Kubota D, Takahashi Y, Yamamichi N, Matsui M, Shimamoto T, Minatsuki C, Nakagawa H, Mizutani S, Tsuji Y, Sakaguchi Y, Tamura N, Yakabi S, Ohki D, Mizutani H, Niimi K, Wada R, Fujishiro M. Analysis of Barrett's Esophagus and Its Risk Factors: A Cross-Sectional Study of 10,122 Subjects at a Japanese Health Examination Center. Digestion 2022; 103:411-420. [PMID: 36075194 PMCID: PMC9808710 DOI: 10.1159/000526154] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 07/18/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Helicobacter pylori eradication is expected to significantly change the prevalence of Barrett's esophagus (BE). However, few reports on this relationship exist. We analyzed the risk factors of BE using the current consensus on length of BE considering H. pylori infection status. METHODS We analyzed 10,122 individuals (5,962 men; mean age = 52.9 ± 9.9 years) who had undergone esophagogastroduodenoscopy as part of a medical checkup. Correlations among factors including H. pylori infectious status, endoscopic findings, and BE ≥1 cm were analyzed. RESULTS Prevalence of BE, long-segment BE, and esophageal adenocarcinoma was 22.5%, 0.014%, and 0%, respectively. Logistic regression analysis showed that the risk factors for BE were hiatal hernia (odds ratio [OR]: 2.89 [2.59-3.24]), female sex (OR: 0.52 [0.46-0.59]), social drinking (OR:0.77 [0.68-0.87]), H. pylori eradication therapy (OR: 1.34 [1.19-1.51]), proton pump inhibitor (PPI) use (OR: 1.52 [1.18-1.96]), bile reflux (OR: 1.18 [1.04-1.33]), age ≥50 years (OR: 1.13 [1.02-1.26]), and nonsteroidal anti-inflammatory drug (NSAID) use (OR: 1.29 [1.02-1.62]). Although reflux esophagitis (RE) was more common in H. pylori-negative patients (17.2%) than in those after H. pylori eradication therapy (11.8%, p < 0.00001), the latter was correlated with BE, disputing RE as a strong risk factor for BE. Therefore, we conducted a subgroup analysis; most of the risk factors except for PPI use (p = 0.75), H2-receptor antagonist use (p = 0.078), and atrophic gastritis absence (p = 0.72) were positively correlated with BE after H. pylori eradication therapy compared with H. pylori-negative status. CONCLUSIONS H. pylori eradication, bile reflux, PPI use, and NSAID use were risk factors for BE along with hiatal hernia, male sex, and older age.
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Affiliation(s)
- Dai Kubota
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan,
| | - Yu Takahashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobutake Yamamichi
- Center for Epidemiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo, Japan
| | - Maki Matsui
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Chihiro Minatsuki
- Infection Control and Prevention Service, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hideki Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Satoru Mizutani
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yosuke Tsuji
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshiki Sakaguchi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naoki Tamura
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Seiichi Yakabi
- Center for International Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Daisuke Ohki
- Infection Control and Prevention Service, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroya Mizutani
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Keiko Niimi
- Center for Epidemiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo, Japan
| | | | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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15
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Zhang ML, Ran LQ, Wu MJ, Jia QC, Qin ZM, Peng YG. NF-κB: A novel therapeutic pathway for gastroesophageal reflux disease? World J Clin Cases 2022; 10:8436-8442. [PMID: 36157831 PMCID: PMC9453379 DOI: 10.12998/wjcc.v10.i24.8436] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 06/16/2022] [Accepted: 07/17/2022] [Indexed: 02/05/2023] Open
Abstract
Although gastroesophageal reflux disease (GERD), a common chronic disease in clinical practice, has been widely studied, its potential adverse impact on patients is still a significant clinical concern. It is necessary to understand the pathogenesis of the disease and choose appropriate treatment according to its mechanism. The pathogenesis of GERD is diverse and complex. As the traditional treatment methods are expensive and ineffective in alleviating symptoms in some patients, new treatment options need to be explored. Our previous study suggested that the activation of nuclear factor-kappa beta (NF-κB) in esophageal mucosa may be related to the injury of epithelial barrier function caused by reflux. Based on the literature and our previous study results, it is speculated that inhibition of NF-κB activation may block the insult of GERD on the esophageal mucosal barrier. NF-κB may play an important role in the development of GERD. This article reviews the pathogenesis of GERD and the relationship between NF-κB and GERD, in order to provide new strategies for the treatment of GERD.
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Affiliation(s)
- Mao-Lin Zhang
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Long-Qing Ran
- Department of Anesthesia, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610019, China
| | - Meng-Jun Wu
- Department of Anesthesia, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610019, China
| | - Qin-Chen Jia
- Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Zhi-Ming Qin
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Yong G Peng
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
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16
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Sugano K, Spechler SJ, El-Omar EM, McColl KEL, Takubo K, Gotoda T, Fujishiro M, Iijima K, Inoue H, Kawai T, Kinoshita Y, Miwa H, Mukaisho KI, Murakami K, Seto Y, Tajiri H, Bhatia S, Choi MG, Fitzgerald RC, Fock KM, Goh KL, Ho KY, Mahachai V, O'Donovan M, Odze R, Peek R, Rugge M, Sharma P, Sollano JD, Vieth M, Wu J, Wu MS, Zou D, Kaminishi M, Malfertheiner P. Kyoto international consensus report on anatomy, pathophysiology and clinical significance of the gastro-oesophageal junction. Gut 2022; 71:1488-1514. [PMID: 35725291 PMCID: PMC9279854 DOI: 10.1136/gutjnl-2022-327281] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/03/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVE An international meeting was organised to develop consensus on (1) the landmarks to define the gastro-oesophageal junction (GOJ), (2) the occurrence and pathophysiological significance of the cardiac gland, (3) the definition of the gastro-oesophageal junctional zone (GOJZ) and (4) the causes of inflammation, metaplasia and neoplasia occurring in the GOJZ. DESIGN Clinical questions relevant to the afore-mentioned major issues were drafted for which expert panels formulated relevant statements and textural explanations.A Delphi method using an anonymous system was employed to develop the consensus, the level of which was predefined as ≥80% of agreement. Two rounds of voting and amendments were completed before the meeting at which clinical questions and consensus were finalised. RESULTS Twenty eight clinical questions and statements were finalised after extensive amendments. Critical consensus was achieved: (1) definition for the GOJ, (2) definition of the GOJZ spanning 1 cm proximal and distal to the GOJ as defined by the end of palisade vessels was accepted based on the anatomical distribution of cardiac type gland, (3) chemical and bacterial (Helicobacter pylori) factors as the primary causes of inflammation, metaplasia and neoplasia occurring in the GOJZ, (4) a new definition of Barrett's oesophagus (BO). CONCLUSIONS This international consensus on the new definitions of BO, GOJ and the GOJZ will be instrumental in future studies aiming to resolve many issues on this important anatomic area and hopefully will lead to better classification and management of the diseases surrounding the GOJ.
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Affiliation(s)
- Kentaro Sugano
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Stuart Jon Spechler
- Division of Gastroenterology, Center for Esophageal Diseases, Baylor University Medical Center, Dallas, Texas, USA
| | - Emad M El-Omar
- Microbiome Research Centre, St George & Sutherland Clinical Campuses, School of Clinical Medicine, Faculty of Medicine & Health, Sydney, New South Wales, Australia
| | - Kenneth E L McColl
- Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Kaiyo Takubo
- Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Takuji Gotoda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Katsunori Iijima
- Department of Gastroenterology, Akita University Graduate School of Medicine, Akita, Japan
| | - Haruhiro Inoue
- Digestive Disease Center, Showa University Koto Toyosu Hospital, Tokyo, Japan
| | - Takashi Kawai
- Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
| | | | - Hiroto Miwa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Kobe, Japan
| | - Ken-Ichi Mukaisho
- Education Center for Medicine and Nursing, Shiga University of Medical Science, Otsu, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Oita University Faculty of Medicine, Yuhu, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hisao Tajiri
- Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | | | - Myung-Gyu Choi
- Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, The Republic of Korea
| | - Rebecca C Fitzgerald
- Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK
| | - Kwong Ming Fock
- Department of Gastroenterology and Hepatology, Duke NUS School of Medicine, National University of Singapore, Singapore
| | | | - Khek Yu Ho
- Department of Medicine, National University of Singapore, Singapore
| | - Varocha Mahachai
- Center of Excellence in Digestive Diseases, Thammasat University and Science Resarch and Innovation, Bangkok, Thailand
| | - Maria O'Donovan
- Department of Histopathology, Cambridge University Hospital NHS Trust UK, Cambridge, UK
| | - Robert Odze
- Department of Pathology, Tuft University School of Medicine, Boston, Massachusetts, USA
| | - Richard Peek
- Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Massimo Rugge
- Department of Medicine DIMED, Surgical Pathology and Cytopathology Unit, University of Padova, Padova, Italy
| | - Prateek Sharma
- Department of Gastroenterology and Hepatology, University of Kansas School of Medicine, Kansas City, Kansas, USA
| | - Jose D Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Friedrich-Alexander University Erlangen, Nurenberg, Germany
| | - Justin Wu
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Duowu Zou
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | - Peter Malfertheiner
- Medizinixhe Klinik und Poliklinik II, Ludwig Maximillian University Klinikum, Munich, Germany
- Klinik und Poliklinik für Radiologie, Ludwig Maximillian University Klinikum, Munich, Germany
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17
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Doukas PG, Vageli DP, Judson BL. The Role of
PARP
‐1 and
NF‐κB
in
Bile‐Induced DNA
Damage and Oncogenic Profile in Hypopharyngeal Cells. Laryngoscope 2022; 133:1146-1155. [PMID: 35791892 DOI: 10.1002/lary.30284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/13/2022] [Accepted: 06/17/2022] [Indexed: 11/10/2022]
Abstract
OBJECTIVES/HYPOTHESIS We recently documented that acidic bile, a gastroesophageal reflux content, can cause invasive hypopharyngeal squamous cell carcinoma, by inducing widespread DNA damage and promoting nuclear factor kappa B (NF-κB)-related oncogenic molecular events. Poly or adenosine diphosphate (ADP)-ribose polymerase-1 (PARP-1), a sensitive sensor of DNA damage, may interact with NF-κB. We hypothesized that PARP-1 is activated in hypopharyngeal cells (HCs) with marked DNA damage caused by acidic bile, hence there is an association between PARP-1 and NF-κB activation or its related oncogenic profile, in this process. STUDY DESIGN In vitro study. METHODS We targeted PARP-1 and NF-κB(p65), using pharmacologic inhibitors, 1.0 μM Rucaparib (AG014699) and 10 μM BAY 11-7082 {3-[4=methylphenyl)sulfonyl]-(2E)-propenenitrile}, respectively, or silencing their gene expression (siRNAs) and used immunofluorescence, luciferase, cell viability, direct enzyme-linked immunosorbent assays, and qPCR analysis to detect the effect of targeting PARP-1 or NF-κB in acidic bile-induced DNA damage, PARP-1, p-NF-κB, and B-cell lymphoma 2 (Bcl-2) expression, as well as NF-κB transcriptional activity, cell survival, and mRNA oncogenic phenotype in HCs. RESULTS We showed that (i) PARP-1 is overexpressed by acidic bile, (ii) targeting NF-κB adequately prevents the acidic bile-induced DNA double-strand breaks (DSBs) by gamma H2A histone family member X (γH2AX), oxidative DNA/RNA damage, PARP-1 overexpression, anti-apoptotic mRNA phenotype, and cell survival, whereas (iii) targeting PARP-1 preserves elevated DNA damage, NF-κB activation, and anti-apoptotic phenotype. CONCLUSION We document for the first time that the activation of PARP-1 is an early event during bile reflux-related head and neck carcinogenesis and that NF-κB can mediate DNA damage and PARP-1 activation. Our data encourage further investigation into how acidic bile-induced activated NF-κB mediates DNA damage in hypopharyngeal carcinogenesis. LEVEL OF EVIDENCE NA Laryngoscope, 133:1146-1155, 2023.
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Affiliation(s)
- Panagiotis G. Doukas
- The Yale Larynx Laboratory, Department of Surgery Section of Otolaryngology, Yale School of Medicine New Haven Connecticut USA
| | - Dimitra P. Vageli
- The Yale Larynx Laboratory, Department of Surgery Section of Otolaryngology, Yale School of Medicine New Haven Connecticut USA
| | - Benjamin L. Judson
- The Yale Larynx Laboratory, Department of Surgery Section of Otolaryngology, Yale School of Medicine New Haven Connecticut USA
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18
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Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat Rev Gastroenterol Hepatol 2022; 19:432-450. [PMID: 35165436 DOI: 10.1038/s41575-021-00566-7] [Citation(s) in RCA: 225] [Impact Index Per Article: 75.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2021] [Indexed: 02/06/2023]
Abstract
Bile acids (BAs) can regulate their own metabolism and transport as well as other key aspects of metabolic homeostasis via dedicated (nuclear and G protein-coupled) receptors. Disrupted BA transport and homeostasis results in the development of cholestatic disorders and contributes to a wide range of liver diseases, including nonalcoholic fatty liver disease and hepatocellular and cholangiocellular carcinoma. Furthermore, impaired BA homeostasis can also affect the intestine, contributing to the pathogenesis of irritable bowel syndrome, inflammatory bowel disease, and colorectal and oesophageal cancer. Here, we provide a summary of the role of BAs and their disrupted homeostasis in the development of gastrointestinal and hepatic disorders and present novel insights on how targeting BA pathways might contribute to novel treatment strategies for these disorders.
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19
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Dosedělová V, Laštovičková M, Ayala-Cabrera JF, Dolina J, Konečný Š, Schmitz OJ, Kubáň P. Quantification and identification of bile acids in saliva by liquid chromatography-mass spectrometry: Possible non-invasive diagnostics of Barret´s esophagus? J Chromatogr A 2022; 1676:463287. [DOI: 10.1016/j.chroma.2022.463287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/24/2022] [Accepted: 06/25/2022] [Indexed: 10/17/2022]
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20
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Vageli DP, Doukas PG, Doukas SG, Tsatsakis A, Judson BL. Noxious Combination of Tobacco Smoke Nitrosamines with Bile, Deoxycholic Acid, Promotes Hypopharyngeal Squamous Cell Carcinoma, via NFκB, In Vivo. Cancer Prev Res (Phila) 2022; 15:297-308. [PMID: 35502554 DOI: 10.1158/1940-6207.capr-21-0529] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/15/2021] [Accepted: 02/21/2022] [Indexed: 11/16/2022]
Abstract
Tobacco smoking is the most known risk factor for hypopharyngeal cancer. Bile reflux has recently been documented as an independent risk factor for NFκB-mediated hypopharyngeal squamous cell carcinoma. However, the carcinogenic effect of tobacco smoke on the hypopharynx and its combination with bile has not yet been proven by direct evidence. We investigated whether in vivo chronic exposure (12-14 weeks) of murine (C57Bl/6J) hypopharyngeal epithelium to tobacco smoke components (TSC) [N-nitrosamines; 4-(N-Methyl-N-Nitrosamino)-1-(3-pyridyl)-1-butanone (0.2 mmol/L), N-nitrosodiethylamine (0.004 mmol/L)], as the sole drinking fluid 5 days per week, along with topically applied (two times/day) bile [deoxycholic acid (0.28 mmol/L)], can accelerate a possible TSC-induced neoplastic process, by enhancing NFκB activation and the associated oncogenic profile, using histologic, IHC, and qPCR analyses. We provide direct evidence of TSC-induced premalignant lesions, which can be exacerbated by the presence of bile, causing invasive carcinoma. The combined chronic exposure of the hypopharynx to TSC with bile causes advanced NFκB activation and profound overexpression of Il6, Tnf, Stat3, Egfr, Wnt5a, composing an aggressive phenotype. We document for the first time the noxious combination of bile with a known risk factor, such as tobacco smoke nitrosamines, in the development and progression of hypopharyngeal cancer, via NFκB, in vivo. The data presented here encourage further investigation into the incidence of upper aerodigestive tract cancers in smokers with bile reflux and the early identification of high-risk individuals in clinical practice. This in vivo model is also suitable for large-scale studies to reveal the nature of inflammatory-associated aerodigestive tract carcinogenesis and its targeted therapy. PREVENTION RELEVANCE Early assessment of bile components in refluxate of tobacco users can prevent the chronic silent progression of upper aerodigestive tract carcinogenesis. This in vivo model indicates that bile reflux might have an additive effect on the tobacco-smoke N-nitrosamines effect and could be suitable for large-scale studies of diagnostic and therapeutic interventions.
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Affiliation(s)
- Dimitra P Vageli
- The Yale Larynx Laboratory, Department of Surgery (Otolaryngology), Yale School of Medicine, New Haven, Connecticut
| | - Panagiotis G Doukas
- The Yale Larynx Laboratory, Department of Surgery (Otolaryngology), Yale School of Medicine, New Haven, Connecticut
| | - Sotirios G Doukas
- The Yale Larynx Laboratory, Department of Surgery (Otolaryngology), Yale School of Medicine, New Haven, Connecticut
- Department of Toxicology, Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, Heraklion, Greece
- Department of Medicine, Rutgers/Saint Peter's University Hospital, New Brunswick, New Jersey
| | - Aristidis Tsatsakis
- Department of Toxicology, Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, Heraklion, Greece
| | - Benjamin L Judson
- The Yale Larynx Laboratory, Department of Surgery (Otolaryngology), Yale School of Medicine, New Haven, Connecticut
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21
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Režen T, Rozman D, Kovács T, Kovács P, Sipos A, Bai P, Mikó E. The role of bile acids in carcinogenesis. Cell Mol Life Sci 2022; 79:243. [PMID: 35429253 PMCID: PMC9013344 DOI: 10.1007/s00018-022-04278-2] [Citation(s) in RCA: 146] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/03/2022] [Accepted: 03/28/2022] [Indexed: 12/17/2022]
Abstract
AbstractBile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; however, other tissues have also the capacity to generate bile acids (e.g. ovaries). Hepatic bile acids are then transported to bile and are subsequently released into the intestines. In the large intestine, a fraction of primary bile acids is converted to secondary bile acids by gut bacteria. The majority of the intestinal bile acids undergo reuptake and return to the liver. A small fraction of secondary and primary bile acids remains in the circulation and exert receptor-mediated and pure chemical effects (e.g. acidic bile in oesophageal cancer) on cancer cells. In this review, we assess how changes to bile acid biosynthesis, bile acid flux and local bile acid concentration modulate the behavior of different cancers. Here, we present in-depth the involvement of bile acids in oesophageal, gastric, hepatocellular, pancreatic, colorectal, breast, prostate, ovarian cancer. Previous studies often used bile acids in supraphysiological concentration, sometimes in concentrations 1000 times higher than the highest reported tissue or serum concentrations likely eliciting unspecific effects, a practice that we advocate against in this review. Furthermore, we show that, although bile acids were classically considered as pro-carcinogenic agents (e.g. oesophageal cancer), the dogma that switch, as lower concentrations of bile acids that correspond to their serum or tissue reference concentration possess anticancer activity in a subset of cancers. Differences in the response of cancers to bile acids lie in the differential expression of bile acid receptors between cancers (e.g. FXR vs. TGR5). UDCA, a bile acid that is sold as a generic medication against cholestasis or biliary surge, and its conjugates were identified with almost purely anticancer features suggesting a possibility for drug repurposing. Taken together, bile acids were considered as tumor inducers or tumor promoter molecules; nevertheless, in certain cancers, like breast cancer, bile acids in their reference concentrations may act as tumor suppressors suggesting a Janus-faced nature of bile acids in carcinogenesis.
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Affiliation(s)
- Tadeja Režen
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Damjana Rozman
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tünde Kovács
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary
| | - Patrik Kovács
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
| | - Adrienn Sipos
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
| | - Péter Bai
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Edit Mikó
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary.
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary.
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22
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Gastroesophageal reflux disease and dental erosion: the role of bile acids. Arch Oral Biol 2022; 139:105429. [DOI: 10.1016/j.archoralbio.2022.105429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 11/30/2022]
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23
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Kolka CM, Webster J, Lepletier A, Winterford C, Brown I, Richards RS, Zelek WM, Cao Y, Khamis R, Shanmugasundaram KB, Wuethrich A, Trau M, Brosda S, Barbour A, Shah AK, Eslick GD, Clemons NJ, Morgan BP, Hill MM. C5b-9 Membrane Attack Complex Formation and Extracellular Vesicle Shedding in Barrett's Esophagus and Esophageal Adenocarcinoma. Front Immunol 2022; 13:842023. [PMID: 35345676 PMCID: PMC8957096 DOI: 10.3389/fimmu.2022.842023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/10/2022] [Indexed: 02/05/2023] Open
Abstract
The early complement components have emerged as mediators of pro-oncogenic inflammation, classically inferred to cause terminal complement activation, but there are limited data on the activity of terminal complement in cancer. We previously reported elevated serum and tissue C9, the terminal complement component, in esophageal adenocarcinoma (EAC) compared to the precursor condition Barrett's Esophagus (BE) and healthy controls. Here, we investigate the level and cellular fates of the terminal complement complex C5b-9, also known as the membrane attack complex. Punctate C5b-9 staining and diffuse C9 staining was detected in BE and EAC by multiplex immunohistofluorescence without corresponding increase of C9 mRNA transcript. Increased C9 and C5b-9 staining were observed in the sequence normal squamous epithelium, BE, low- and high-grade dysplasia, EAC. C5b-9 positive esophageal cells were morphologically intact, indicative of sublytic or complement-evasion mechanisms. To investigate this at a cellular level, we exposed non-dysplastic BE (BAR-T and CP-A), high-grade dysplastic BE (CP-B and CP-D) and EAC (FLO-1 and OE-33) cell lines to the same sublytic dose of immunopurified human C9 (3 µg/ml) in the presence of C9-depleted human serum. Cellular C5b-9 was visualized by immunofluorescence confocal microscopy. Shed C5b-9 in the form of extracellular vesicles (EV) was measured in collected conditioned medium using recently described microfluidic immunoassay with capture by a mixture of three tetraspanin antibodies (CD9/CD63/CD81) and detection by surface-enhanced Raman scattering (SERS) after EV labelling with C5b-9 or C9 antibody conjugated SERS nanotags. Following C9 exposure, all examined cell lines formed C5b-9, internalized C5b-9, and shed C5b-9+ and C9+ EVs, albeit at varying levels despite receiving the same C9 dose. In conclusion, these results confirm increased esophageal C5b-9 formation during EAC development and demonstrate capability and heterogeneity in C5b-9 formation and shedding in BE and EAC cell lines following sublytic C9 exposure. Future work may explore the molecular mechanisms and pathogenic implications of the shed C5b-9+ EV.
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Affiliation(s)
- Cathryn M. Kolka
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Julie Webster
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Ailin Lepletier
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Clay Winterford
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Ian Brown
- Envoi Pathology, Herston, QLD, Australia
| | | | - Wioleta M. Zelek
- Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Yilang Cao
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Ramlah Khamis
- Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, QLD, Australia
| | - Karthik B. Shanmugasundaram
- Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, QLD, Australia
| | - Alain Wuethrich
- Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, QLD, Australia
| | - Matt Trau
- Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, QLD, Australia
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
| | - Sandra Brosda
- University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, St Lucia, QLD, Australia
| | - Andrew Barbour
- University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, St Lucia, QLD, Australia
| | - Alok K. Shah
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Guy D. Eslick
- National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Digestive Health, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
| | - Nicholas J. Clemons
- Cancer Research Division, Peter MaCallum Cancer Centre, Melbourne VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | - B. Paul Morgan
- Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Michelle M. Hill
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
- University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, St Lucia, QLD, Australia
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24
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Perez N, Chambert K, Ribadeneira M, Currie MG, Chen Y, Kessler MM. Differential Bile Acid Detection in Refractory GERD Patient Saliva Using a Simple and Sensitive Liquid Chromatography Tandem Mass Spectrometry Approach. J Clin Gastroenterol 2022; 56:218-223. [PMID: 33731598 DOI: 10.1097/mcg.0000000000001525] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 02/02/2021] [Indexed: 12/10/2022]
Abstract
GOALS The aim was to measure bile acids in human saliva using a sensitive ultraperformance liquid chromatography tandem mass spectrometry analysis method to distinguish quantitative differences in refractory gastroesophageal reflux disease (GERD) patients as compared with proton pump inhibitor (PPI) controlled GERD patients and healthy volunteers. STUDY Human saliva samples were analyzed from 2 separate studies. The first a meal-controlled pilot, in which premeal and postmeal saliva samples were analyzed from 20 healthy subjects and 20 patients with GERD symptoms controlled by PPIs. In a subsequent exploratory study, saliva was collected from 34 patients with continuing GERD symptoms despite PPI treatment (refractory GERD), 30 healthy subjects, and 30 PPI-controlled GERD patients at ≥4 hours postmeal. RESULTS In the meal-controlled pilot study, both healthy subjects and patients with PPI-controlled GERD, had total saliva bile acid increase for the first hour after consumption of a meal and returned to baseline levels 4 hours later. There was no difference in bile acid levels between the 2 groups. In the exploratory study, the saliva from patients with refractory GERD had statistically significant higher levels of total bile acid concentration compared with those of healthy volunteers and patients with PPI-controlled GERD (P=0.0181). CONCLUSIONS Bile acids can be detected and accurately quantitated in human saliva using a sensitive ultraperformance liquid chromatography tandem mass spectrometry assay. Increases above threshold could indicate an underlying disease.This method could potentially be used to evaluate biliary reflux as an underlying pathophysiology of refractory GERD.
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25
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Vageli DP, Doukas SG, Doukas PG, Judson BL. Bile reflux and hypopharyngeal cancer (Review). Oncol Rep 2021; 46:244. [PMID: 34558652 PMCID: PMC8485019 DOI: 10.3892/or.2021.8195] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 08/24/2021] [Indexed: 12/26/2022] Open
Abstract
Laryngopharyngeal reflux, a variant of gastroesophageal reflux disease, has been considered a risk factor in the development of hypopharyngeal cancer. Bile acids are frequently present in the gastroesophageal refluxate and their effect has been associated with inflammatory and neoplastic changes in the upper aerodigestive tract. Recent in vitro and in vivo studies have provided direct evidence of the role of acidic bile refluxate in hypopharyngeal carcinogenesis and documented the crucial role of NF-κB as a key mediator of early oncogenic molecular events in this process and also suggested a contribution of STAT3. Acidic bile can cause premalignant changes and invasive squamous cell cancer in the affected hypopharynx accompanied by DNA damage, elevated p53 expression and oncogenic mRNA and microRNA alterations, previously linked to head and neck cancer. Weakly acidic bile can also increase the risk for hypopharyngeal carcinogenesis by inducing DNA damage, exerting anti-apoptotic effects and causing precancerous lesions. The most important findings that strongly support bile reflux as an independent risk factor for hypopharyngeal cancer are presented in the current review and the underlying mechanisms are provided.
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Affiliation(s)
- Dimitra P Vageli
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
| | - Sotirios G Doukas
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
| | - Panagiotis G Doukas
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
| | - Benjamin L Judson
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
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26
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Basnayake C, Geeraerts A, Pauwels A, Koek G, Vaezi M, Vanuytsel T, Tack J. Systematic review: duodenogastroesophageal (biliary) reflux prevalence, symptoms, oesophageal lesions and treatment. Aliment Pharmacol Ther 2021; 54:755-778. [PMID: 34313333 DOI: 10.1111/apt.16533] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/20/2021] [Accepted: 07/01/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND The prevalence of duodenogastroesophageal reflux (DGER) and its effect on symptoms and oesophageal lesions in gastroesophageal reflux disease (GERD) is unclear. AIMS To conduct a systematic review to determine the prevalence of DGER among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER. METHODS We searched Pubmed and MEDLINE for full text, English language articles until October 2020 that evaluated DGER prevalence among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER. RESULTS We identified 3891 reports and included 35 which analysed DGER prevalence in GERD, 15 which evaluated its effect in non-erosive reflux disease (NERD), 17 on erosive oesophagitis, 23 in Barrett's, and 13 which evaluated the treatment of DGER. The prevalence of DGER, when evaluated by Bilitec, among all GERD patients ranged from 10% to 97%, in NERD 10%-63%, in erosive oesophagitis 22%-80% and in Barrett's 50%-100%. There were no differences in the presence or degree of DGER among patients who were asymptomatic or symptomatic on proton pump inhibitors (PPI). The most commonly evaluated treatments for DGER were PPIs and DGER reduced post-PPI therapy in all studies. CONCLUSIONS The prevalence of DGER increased with more advanced oesophageal lesions and did not explain persisting symptoms among patients taking PPI therapy. PPIs appear to be effective in the treatment of DGER. DGER remains an important consideration in patients with GERD and future therapies deserve more study.
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Affiliation(s)
- Chamara Basnayake
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium.,St Vincent's Hospital & University of Melbourne, Melbourne, VIC, Australia
| | - Annelies Geeraerts
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Ans Pauwels
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Ger Koek
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Michael Vaezi
- Vanderbilt University Medical Center, Nashville, TN, USA
| | - Tim Vanuytsel
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Jan Tack
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
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27
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Alkhayyat M, Kumar P, Sanaka KO, Thota PN. Chemoprevention in Barrett's esophagus and esophageal adenocarcinoma. Therap Adv Gastroenterol 2021; 14:17562848211033730. [PMID: 34434254 PMCID: PMC8381453 DOI: 10.1177/17562848211033730] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 06/29/2021] [Indexed: 02/04/2023] Open
Abstract
There has been a dramatic increase in the incidence of Barrett's esophagus and esophageal adenocarcinoma over the past several decades with a continued rise expected in the future. Several strategies have been developed for screening and surveillance of patients with Barrett's esophagus and endoscopic treatment of Barrett's associated dysplasia and early esophageal cancer; however, they have not made a substantial impact on the incidence of cancer. Herein, chemoprevention becomes an attractive idea for reducing the incidence of cancer in Barrett's patients. Several agents appear promising in preclinical and observational studies but very few have been evaluated in randomized controlled trials. Strongest evidence to date is available for proton-pump inhibitors and Aspirin that have been evaluated in a large randomized controlled trial. Other agents such as statins, metformin, ursodeoxycholic acid, and dietary supplements have insufficient evidence for chemoprevention in Barrett's patients.
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Affiliation(s)
- Motasem Alkhayyat
- Department of Internal Medicine, Cleveland
Clinic, Cleveland, OH, USA
| | - Prabhat Kumar
- Department of Gastroenterology and Hepatology,
Cleveland Clinic, Cleveland, OH, USA
| | - Krishna O. Sanaka
- Department of Gastroenterology and Hepatology,
Cleveland Clinic, Cleveland, OH, USA
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28
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Yu X, Hu Y, Yu M, Undem BJ, Yu S. Deoxycholic acid activates and sensitizes vagal nociceptive afferent C-fibers in guinea pig esophagus. Am J Physiol Gastrointest Liver Physiol 2021; 321:G149-G156. [PMID: 34160291 PMCID: PMC8410107 DOI: 10.1152/ajpgi.00187.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Bile acid reflux in the esophagus plays a role in the pathogenesis of certain esophageal disorders, where it can induce esophageal pain and heartburn. The present study aimed to determine whether bile acid, deoxycholic acid (DCA), directly activates and sensitizes esophageal vagal nociceptive afferent C-fiber subtypes. DCA-elicited effects on vagal nodose and jugular neurons were studied by calcium imaging. Its effects on esophageal-labeled nodose and jugular neurons were then determined by patch-clamp recording. At nodose and jugular C-fiber nerve endings in the esophagus, DCA-evoked action potentials (APs) were compared by extracellular single-unit recordings in ex vivo esophageal-vagal preparations. DCA application induced calcium influxes in nodose and jugular neurons and elicited inward currents in esophageal-labeled nodose and jugular neurons. In the presence of DCA, the current densities elicited by capsaicin were enhanced in those labeled neurons. Consistently, DCA perfusion at nerve terminals in the esophagus evoked APs in about 50% of esophageal nodose and jugular C-fibers. In DCA-sensitive C-fibers, DCA perfusion also sensitized the fibers such that the subsequent response to capsaicin was amplified. Collectively, these results provide new evidence that DCA directly activates and sensitizes nociceptive nodose and jugular C-fibers in the esophagus. Such activation and sensitization effects may contribute to bile acid-induced esophageal nociceptive symptoms that are refractory to proton-pump inhibitor therapy.NEW & NOTEWORTHY Bile acid reflux in the esophagus can induce pain and heartburn in certain esophageal disorders, but the underlying neuronal mechanism is still unclear. The present study demonstrated that bile acid, deoxycholic acid (DCA), directly activates esophageal vagal afferent nodose and jugular nociceptive C-fibers and sensitizes their response to capsaicin. Such effects may contribute to bile acid-induced esophageal nociceptive symptoms that refractory to proton-pump inhibitors (PPIs) therapy.
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Affiliation(s)
- Xiaoyun Yu
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Youtian Hu
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mingwei Yu
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Bradley J. Undem
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Shaoyong Yu
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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29
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The integrity and barrier function of porcine vocal fold epithelium: its susceptibility to damage by deoxycholic acid compared with pepsin. Eur Arch Otorhinolaryngol 2021; 278:4893-4899. [PMID: 34292400 DOI: 10.1007/s00405-021-06997-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022]
Abstract
PURPOSE In this study, we aim to systematically evaluate the damaging role of gastric (pepsin and acid) and duodenal ingredients (bile acids) on vocal fold epithelium in excised porcine larynges. METHODS Fresh ex vivo porcine larynges were exposed to one of five experimental conditions for 1 h. These conditions will be referred to as alkaline deoxycholic acid, acidic pepsin, acid pH3 only, acid pH5 only, and control, respectively. A Franz diffusing cell was used to evaluate the barrier function of vocal fold epithelium by measuring the permeability to fluorescein isothiocyanate dextran of 4 kDa. Histological changes were observed using transmission electron microscopy. RESULTS After immersing the fresh porcine larynges in the five solution groups, we found that the vocal fold epithelium in the deoxycholic acid group had more permeability to FD4 than the pepsin group (P < 0.001). Fragmentation and desquamation of dead cell layers were observed in both the pepsin and deoxycholic acid groups, but were more severe in the deoxycholic acid group than the pepsin group. The thickness of the dead epithelial cell layer gradually increased with increasing acid concentration (P < 0.05). Additionally, the thickness of the dead epithelial cell layer in the deoxycholic acid group was significantly higher than that in the pepsin group (P < 0.01). CONCLUSION Deoxycholic acid in a weakly acidic condition is more likely than pepsin to induce apoptosis in ex vivo porcine vocal fold epithelium, destroy the link proteins between epithelial cells, and affect their integrity and barrier function.
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30
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Dean AE, Reichardt F, Anakk S. Sex differences feed into nuclear receptor signaling along the digestive tract. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166211. [PMID: 34273530 DOI: 10.1016/j.bbadis.2021.166211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/14/2021] [Accepted: 07/05/2021] [Indexed: 02/07/2023]
Abstract
Sex differences in physiology are noted in clinical and animal studies. However, mechanisms underlying these observed differences between males and females remain elusive. Nuclear receptors control a wide range of physiological pathways and are expressed in the gastrointestinal tract, including the mouth, stomach, liver and intestine. We investigated the literature pertaining to ER, AR, FXR, and PPAR regulation and highlight the sex differences in nutrient metabolism along the digestive system. We chose these nuclear receptors based on their metabolic functions, and hormonal actions. Intriguingly, we noted an overlap in target genes of ER and FXR that modulate mucosal integrity and GLP-1 secretion, whereas overlap in target genes of PPARα with ER and AR modulate lipid metabolism. Sex differences were seen not only in the basal expression of nuclear receptors, but also in activation as their endogenous ligand concentrations fluctuate depending on nutrient availability. Finally, in this review, we speculate that interactions between the nuclear receptors may influence overall metabolic decisions in the gastrointestinal tract in a sex-specific manner.
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Affiliation(s)
- Angela E Dean
- Division of Nutritional Sciences, University of Illinois Urbana Champaign, Urbana, IL, United States of America
| | - François Reichardt
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America
| | - Sayeepriyadarshini Anakk
- Division of Nutritional Sciences, University of Illinois Urbana Champaign, Urbana, IL, United States of America; Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America; Cancer center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America.
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31
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Sifrim D, Penagini R. Duodenogastroesophageal Reflux. THE ESOPHAGUS 2021:394-418. [DOI: 10.1002/9781119599692.ch23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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32
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De A, Zhou J, Liu P, Huang M, Gunewardena S, Mathur SC, Christenson LK, Sharma M, Zhang Q, Bansal A. Forkhead box F1 induces columnar phenotype and epithelial-to-mesenchymal transition in esophageal squamous cells to initiate Barrett's like metaplasia. J Transl Med 2021; 101:745-759. [PMID: 33495575 PMCID: PMC9296259 DOI: 10.1038/s41374-021-00534-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 12/22/2020] [Accepted: 12/28/2020] [Indexed: 11/08/2022] Open
Abstract
Multiple genome-wide association studies (GWAS) have linked Forkhead Box F1 (FOXF1) to Barrett's esophagus (BE). Understanding whether FOXF1 is involved in initiation of Barrett's metaplasia could allow FOXF1 to be used for risk stratification and for therapy. Two-dimensional cell cultures and three-dimensional organoid cultures and well-annotated human biopsies were used to determine the role of FOXF1 in BE pathogenesis. Multiple established esophageal squamous and BE cell lines were tested in gain- and loss-of-function studies. Initiation of a BE-like metaplastic change was evaluated by measuring characteristic cytokeratins and global gene expression profiling and by culturing organoids. Epithelial-mesenchymal transition (EMT) was evaluated by immunostaining for E-cadherin, vimentin and Snail, and by cell motility assay. Columnar esophageal epithelium of BE patients exhibited higher expression of FOXF1 compared to normal squamous esophageal epithelium of GERD patients (P < 0.001). Acidic bile salts induced nuclear FOXF1 in esophageal squamous cells. FOXF1 overexpression in normal esophageal squamous cells: (a) increased columnar cytokeratins and decreased squamous cytokeratins, (b) converted squamous organoids to glandular organoids, and (c) switched global gene profiles to resemble that of human BE epithelium (P = 2.1685e - 06 for upregulated genes and P = 8.3378e - 09 for downregulated genes). FOXF1 inhibition in BE cell lines led to loss of BE differentiation markers, CK7, and mucin 2. Also, FOXF1 induced EMT and promoted cell motility in normal esophageal squamous epithelial cells. FOXF1-induced genes mapped to pathways such as Cancer, Cellular Assembly and Organization, DNA Replication, Recombination, and Repair. In conclusion, FOXF1 promotes a BE-like columnar phenotype and cell motility in esophageal squamous epithelial cells, which may have a critical role in BE development. FOXF1 should be studied further as a biomarker for BE and as a target for BE treatment.
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Affiliation(s)
- Alok De
- Midwest Veterans' Biomedical Research Foundation (MVBRF), Kansas City, MO, USA
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Jianping Zhou
- Midwest Veterans' Biomedical Research Foundation (MVBRF), Kansas City, MO, USA
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Pi Liu
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, TX, 75246, USA
| | - Manling Huang
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, TX, 75246, USA
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Sharad C Mathur
- Department of Pathology and Laboratory Medicine, Veterans Affairs Medical Center, Kansas City, MO, USA
- The University of Kansas Medical Center, Kansas City, KS, USA
| | - Lane K Christenson
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Mukut Sharma
- Midwest Veterans' Biomedical Research Foundation (MVBRF), Kansas City, MO, USA
- Research and Development Service, Kansas City Veterans Affairs Medical Center, Kansas City, MO, USA
| | - Qiuyang Zhang
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, TX, 75246, USA.
| | - Ajay Bansal
- Division of Gastroenterology and Hepatology, The University of Kansas Medical Center, Kansas City, KS, USA.
- Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO, USA.
- The University of Kansas Cancer Center, Kansas City, KS, USA.
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Wei M, Zhao L, Lv J, Li X, Zhou G, Fan B, Shen X, Zhao D, Xue F, Wang J, Zhang T. The mediation effect of serum metabolites on the relationship between long-term smoking exposure and esophageal squamous cell carcinoma. BMC Cancer 2021; 21:415. [PMID: 33858379 PMCID: PMC8050928 DOI: 10.1186/s12885-021-08151-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 04/05/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Long-term smoking exposure will increase the risk of esophageal squamous cell carcinoma (ESCC), whereas the mechanism is still unclear. We conducted a cross-sectional study to explore whether serum metabolites mediate the occurrence of ESCC caused by cigarette smoking. METHODS Serum metabolic profiles and lifestyle information of 464 participants were analyzed. Multiple logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of smoking exposure to ESCC risk. High-dimensional mediation analysis and univariate mediation analysis were performed to screen potential intermediate metabolites of smoking exposure for ESCC. RESULTS Ever smoking was associated with a 3.11-fold increase of ESCC risk (OR = 3.11, 95% CI 1.63-6.05), and for each cigarette-years increase in smoking index, ESCC risk increased by 56% (OR = 1.56, 95% CI 1.18-2.13). A total of 5 metabolites were screened as mediators by high-dimensional mediation analysis. In addition, glutamine, histidine, and cholic acid were further proved existing mediation effects according to univariate mediation analysis. And the proportions of mediation of histidine and glutamine were 40.47 and 30.00%, respectively. The mediation effect of cholic acid was 8.98% according to the analysis of smoking index. CONCLUSIONS Our findings suggest that cigarette smoking contributed to incident ESCC, which may be mediated by glutamine, histidine and cholic acid.
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Affiliation(s)
- Mengke Wei
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, PO Box 100, 44 Wenhua Xi Rd, Jinan, 250012, Shandong, China
| | - Lihong Zhao
- Tumor Preventative and Therapeutic Base of Shandong Province, Feicheng People's Hospital, Feicheng, 271600, China
| | - Jiali Lv
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, PO Box 100, 44 Wenhua Xi Rd, Jinan, 250012, Shandong, China
| | - Xia Li
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, PO Box 100, 44 Wenhua Xi Rd, Jinan, 250012, Shandong, China.,Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China
| | - Guangshuai Zhou
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, PO Box 100, 44 Wenhua Xi Rd, Jinan, 250012, Shandong, China
| | - Bingbing Fan
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, PO Box 100, 44 Wenhua Xi Rd, Jinan, 250012, Shandong, China
| | - Xiaotao Shen
- Interdisciplinary Research Center on Biology and Chemistry, and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China
| | - Deli Zhao
- Tumor Preventative and Therapeutic Base of Shandong Province, Feicheng People's Hospital, Feicheng, 271600, China
| | - Fuzhong Xue
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, PO Box 100, 44 Wenhua Xi Rd, Jinan, 250012, Shandong, China
| | - Jialin Wang
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, PO Box 100, 44 Wenhua Xi Rd, Jinan, 250012, Shandong, China.,Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China
| | - Tao Zhang
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, PO Box 100, 44 Wenhua Xi Rd, Jinan, 250012, Shandong, China.
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Wada Y, Mukaisho KI, Kanai S, Nakayama T, Fukuda M, Mizukami K, Okimoto T, Kodama M, Sugihara H, Murakami K, Kushima R. Development of Pancreatic Acinar Cell Metaplasia During Gastric Repair in a Rat Duodenal Contents Reflux Model. Dig Dis Sci 2021; 66:1072-1079. [PMID: 32440745 PMCID: PMC7990820 DOI: 10.1007/s10620-020-06342-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 05/12/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND We previously reported the development of pancreatic acinar cell metaplasia (PACM) in the glandular stomach of a duodenal contents reflux model (reflux model). AIMS We aimed to investigate the characteristics and histogenesis of PACM using a reflux model. METHODS A reflux model was created using 8-week-old male Wistar rats, which were killed up to 30 weeks postoperatively. Histological examination was performed to analyze the glandular stomach-jejunal anastomosis. Furthermore, electron microscopic images of PACM samples were compared with pancreatic and gastric glands removed from rats that had not undergone surgery. Immunostaining for α-amylase, HIK1083, TFF2, and Ki-67 was performed, and double fluorescent staining was carried out using antibodies against α-amylase and HIK1083, or α-amylase and TFF2. RESULTS In all reflux model rats, PACM was observed proximal to the glandular stomach-jejunal anastomosis, surrounded by pseudopyloric metaplasia. The number of chief cells was decreased in the deep part of the gland, where PACM occurred. Electron microscopy showed that PACM cells had greater numbers of rough endoplasmic reticulum tubules than chief cells, and exhibited pancreatic acinar cell morphology. Upon immunochemical staining, the regenerative foveolar epithelium and part of the pseudopyloric glands stained strongly positive for TFF2, whereas PACM cells were only weakly positive. Double fluorescent staining identified early lesions of PACM in the neck, which were double positive for α-amylase and TFF2, but negative for HIK1083. CONCLUSIONS PACM could be induced by duodenal contents reflux. PACM originates from stem cells located in the neck of oxyntic glands during gastric mucosal regeneration.
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Affiliation(s)
- Yasuhiro Wada
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
- Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Otsu, Shiga, 520-2192, Japan
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Ken-Ichi Mukaisho
- Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Otsu, Shiga, 520-2192, Japan.
| | - Shunpei Kanai
- Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Otsu, Shiga, 520-2192, Japan
| | - Takahisa Nakayama
- Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Otsu, Shiga, 520-2192, Japan
| | - Masahide Fukuda
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
| | - Kazuhiro Mizukami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
| | - Tadayoshi Okimoto
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
| | - Masaaki Kodama
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
| | - Hiroyuki Sugihara
- Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Otsu, Shiga, 520-2192, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
| | - Ryoji Kushima
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
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A Systematic Review of the Methods of Assessment of Gastro-Oesophageal Reflux in Anaesthetized Dogs. Animals (Basel) 2021; 11:ani11030852. [PMID: 33803871 PMCID: PMC8003202 DOI: 10.3390/ani11030852] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/15/2021] [Accepted: 03/16/2021] [Indexed: 01/01/2023] Open
Abstract
Simple Summary Regurgitation and gastro-oesophageal reflux (GOR) are common complications in dogs under anaesthesia. We reviewed the definitions and methods of GOR assessment in anaesthetized dogs published in 22 scientific papers to assess if studies were comparable (i.e., looking at the same thing). The definition of GOR implied the presence of fluids not reaching the mouth or nose in the oesophagus in all studies. Most studies measured the acidity in the oesophagus to state if fluids were present or not. The probes were not always placed in the same location and definitions varied. This means that it is complicated to compare findings of the different studies. Abstract We reviewed the definitions and methods of assessment of gastro-oesophageal reflux (GOR) in anaesthetized dogs. Three databases were used. Titles and abstracts were screened by two of the authors independently. A total of 22 studies was included in the analysis. The definition of GOR implied the presence of fluids not reaching the mouth or nose in the oesophagus in all studies. Most studies considered a change in pH using oesophageal pH meters as the sole method of assessment. Calibration of the pH probe was inconsistently reported. The position of the tip of the oesophageal probe was inconsistent and not always precisely described. The correct positioning in the intended location was verified in a limited number of studies. Some studies considered that GOR had happened for changes in pH below 4.0 or above 7.5 while others considered that GOR had happened when the pH dropped below 4.0 only. Some studies stated that the pH change had to be sustained for a minimum period of time (20 or 30 s) whereas others did not mention any duration. The variability of definitions and methods of assessment of GOR in anaesthetized dogs precludes meaningful comparison of the findings. Re-evaluation and uniformization of the methods appear necessary.
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Elliott JA, Reynolds JV. Visceral Obesity, Metabolic Syndrome, and Esophageal Adenocarcinoma. Front Oncol 2021; 11:627270. [PMID: 33777773 PMCID: PMC7994523 DOI: 10.3389/fonc.2021.627270] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 02/19/2021] [Indexed: 12/16/2022] Open
Abstract
Esophageal adenocarcinoma (EAC) represents an exemplar of obesity-associated carcinogenesis, with a progressive increase in EAC risk with increased body mass index. In this context, there is increased focus on visceral adipose tissue and associated metabolic dysfunction, including hypertension, diabetes mellitus and hyperlipidemia, or combinations of these in the metabolic syndrome. Visceral obesity (VO) may promote EAC via both directly impacting on gastro-esophageal reflux disease and Barrett's esophagus, as well as via reflux-independent effects, involving adipokines, growth factors, insulin resistance, and the microbiome. In this review these pathways are explored, including the impact of VO on the tumor microenvironment, and on cancer outcomes. The current evidence-based literature regarding the role of dietary, lifestyle, pharmacologic and surgical interventions to modulate the risk of EAC is explored.
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Affiliation(s)
- Jessie A Elliott
- Trinity St. James's Cancer Institute, Trinity College Dublin and St. James's Hospital, Dublin, Ireland
| | - John V Reynolds
- Trinity St. James's Cancer Institute, Trinity College Dublin and St. James's Hospital, Dublin, Ireland
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Weakly Acidic Bile Is a Risk Factor for Hypopharyngeal Carcinogenesis Evidenced by DNA Damage, Antiapoptotic Function, and Premalignant Dysplastic Lesions In Vivo. Cancers (Basel) 2021; 13:cancers13040852. [PMID: 33670587 PMCID: PMC7923205 DOI: 10.3390/cancers13040852] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/13/2021] [Accepted: 02/14/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The etiologic role of biliary reflux in hypopharyngeal cancer is supported by clinical data. Although, reflux episodes often occur at pH 4.0, they can also occur at weakly acidic pH (5.5–6.0). The carcinogenic effect of bile at strongly acidic pH (pH 3.0) was recently documented in vivo. Here, we provide novel in vivo evidence that a weakly acidic pH of 5.5, similarly to a strongly acidic pH of 3.0, increases the risk of bile-related hypopharyngeal neoplasia. We document that chronic exposure of hypopharyngeal mucosa to bile at pH 5.5 promotes premalignant lesions with DNA damage, NF-κB activation, and deregulated mRNA and miRNA phenotypes, including Bcl-2 and miR-451a. The oncogenic effects of bile over a wider pH range suggests that antacid therapy may be insufficient to fully modify the effects of a bile induced oncogenic effect. Abstract Background: There is recent in vivo discovery documenting the carcinogenic effect of bile at strongly acidic pH 3.0 in hypopharynx, while in vitro data demonstrate that weakly acidic bile (pH 5.5) has a similar oncogenic effect. Because esophageal refluxate often occurs at pH > 4.0, here we aim to determine whether weakly acidic bile is also carcinogenic in vivo. Methods: Using 32 wild-type mice C57B16J, we performed topical application of conjugated primary bile acids with or without unconjugated secondary bile acid, deoxycholic acid (DCA), at pH 5.5 and controls, to hypopharyngeal mucosa (HM) twice per day, for 15 weeks. Results: Chronic exposure of HM to weakly acidic bile, promotes premalignant lesions with microinvasion, preceded by significant DNA/RNA oxidative damage, γH2AX (double strand breaks), NF-κB and p53 expression, overexpression of Bcl-2, and elevated Tnf and Il6 mRNAs, compared to controls. Weakly acidic bile, without DCA, upregulates the “oncomirs”, miR-21 and miR-155. The presence of DCA promotes Egfr, Wnt5a, and Rela overexpression, and a significant downregulation of “tumor suppressor” miR-451a. Conclusion: Weakly acidic pH increases the risk of bile-related hypopharyngeal neoplasia. The oncogenic properties of biliary esophageal reflux on the epithelium of the upper aerodigestive tract may not be fully modified when antacid therapy is applied. We believe that due to bile content, alternative therapeutic strategies using specific inhibitors of relevant molecular pathways or receptors may be considered in patients with refractory GERD.
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Impact of Deoxycholic Acid on Oesophageal Adenocarcinoma Invasion: Effect on Matrix Metalloproteinases. Int J Mol Sci 2020; 21:ijms21218042. [PMID: 33126685 PMCID: PMC7672620 DOI: 10.3390/ijms21218042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 10/27/2020] [Indexed: 12/29/2022] Open
Abstract
Bile acids (BAs) have been implicated in the development of oesophagitis, Barrett’s oesophagus and oesophageal adenocarcinoma (OAC). However, whether BAs promote cancer invasiveness has not been elucidated. We evaluated the role of BAs, in particular deoxycholic acid (DCA), in OAC invasion. Migration and invasiveness in untreated and BA-treated oesophageal SKGT-4 cancer cells were evaluated. Activity and expression of different matrix metalloproteinases (MMPs) were determined by zymography, ELISA, PCR and Western blot. Finally, human OAC tissues were stained for MMP-10 by immunohistochemistry. It was found that SKGT-4 cells incubated with low concentrations of DCA had a significant increase in invasion. In addition, MMP-10 mRNA and protein expression were also increased in the presence of DCA. MMP-10 was found to be highly expressed both in-vitro and in-vivo in neoplastic OAC cells relative to non-neoplastic squamous epithelial cells. Our results show that DCA promotes OAC invasion and MMP-10 overexpression. This study will advance our understanding of the pathophysiological mechanisms involved in human OAC and shows promise for the development of new therapeutic strategies.
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Sharma P, Yadlapati R. Pathophysiology and treatment options for gastroesophageal reflux disease: looking beyond acid. Ann N Y Acad Sci 2020; 1486:3-14. [PMID: 33015827 DOI: 10.1111/nyas.14501] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/24/2020] [Accepted: 09/01/2020] [Indexed: 12/14/2022]
Abstract
Gastroesophageal reflux disease (GERD) is a disorder due to the retrograde flow of refluxate into the esophagus. Although GERD is a common clinical diagnosis, its pathogenesis is quite complex. As a result of its multifactorial development, many patients continue to experience adverse symptoms due to GERD despite prolonged acid suppression with proton pump inhibitor therapy. The pathogenesis of GERD involves an interplay of chemical, mechanical, psychologic, and neurologic mechanisms, which contribute to symptom presentation, diagnosis, and treatment. As such, GERD should be approached as a disorder beyond acid. This review will investigate the major factors that contribute to the development of GERD, including factors related to the refluxate, esophageal defenses, and factors that promote pathologic reflux into the esophagus. In reviewing GERD pathogenesis, this paper will highlight therapeutic advances, with mention of future opportunities of study when approaching GERD.
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Affiliation(s)
- Priya Sharma
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Rena Yadlapati
- Division of Gastroenterology, University of California San Diego School of Medicine, Center for Esophageal Diseases, La Jolla, California
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40
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Agostinis C, Bossi F, Mangogna A, Balduit A, Pacor M, Giacomello E, Belmonte B, Greco D, Rodolico V, Voinovich D, De Seta F, Ricci G, Bulla R. Protective and regenerative effects of a novel medical device against esophageal mucosal damage using in vitro and ex vivo models. Biomed Pharmacother 2020; 131:110752. [PMID: 33152918 DOI: 10.1016/j.biopha.2020.110752] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/26/2020] [Accepted: 09/10/2020] [Indexed: 12/18/2022] Open
Abstract
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.
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Affiliation(s)
- Chiara Agostinis
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.
| | - Fleur Bossi
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
| | - Alessandro Mangogna
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
| | - Andrea Balduit
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Micol Pacor
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | | | - Beatrice Belmonte
- Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy
| | - Daniele Greco
- Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy
| | - Vito Rodolico
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Dario Voinovich
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste, Italy
| | - Francesco De Seta
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy; Department of Medical, Surgical and Health Science, University of Trieste, Trieste, Italy
| | - Giuseppe Ricci
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy; Department of Medical, Surgical and Health Science, University of Trieste, Trieste, Italy
| | - Roberta Bulla
- Department of Life Sciences, University of Trieste, Trieste, Italy.
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Korbut E, Janmaat VT, Wierdak M, Hankus J, Wójcik D, Surmiak M, Magierowska K, Brzozowski T, Peppelenbosch MP, Magierowski M. Molecular Profile of Barrett's Esophagus and Gastroesophageal Reflux Disease in the Development of Translational Physiological and Pharmacological Studies. Int J Mol Sci 2020; 21:6436. [PMID: 32899384 PMCID: PMC7504401 DOI: 10.3390/ijms21176436] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 08/31/2020] [Accepted: 09/01/2020] [Indexed: 02/08/2023] Open
Abstract
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, KRT6A, 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.
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Affiliation(s)
- Edyta Korbut
- Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland; (E.K.); (M.W.); (D.W.); (M.S.); (K.M.); (T.B.)
| | - Vincent T Janmaat
- Department of Gastroenterology and Hepatology, Erasmus MC—University Medical Center Rotterdam, 3015 CN Rotterdam, The Netherlands; (V.T.J.); (M.P.P.)
| | - Mateusz Wierdak
- Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland; (E.K.); (M.W.); (D.W.); (M.S.); (K.M.); (T.B.)
- 2nd Department of General Surgery, Jagiellonian University Medical College, 30-688 Cracow, Poland
| | - Jerzy Hankus
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
| | - Dagmara Wójcik
- Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland; (E.K.); (M.W.); (D.W.); (M.S.); (K.M.); (T.B.)
| | - Marcin Surmiak
- Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland; (E.K.); (M.W.); (D.W.); (M.S.); (K.M.); (T.B.)
- Department of Internal Medicine, Jagiellonian University Medical College, 31-066 Cracow, Poland
| | - Katarzyna Magierowska
- Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland; (E.K.); (M.W.); (D.W.); (M.S.); (K.M.); (T.B.)
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland; (E.K.); (M.W.); (D.W.); (M.S.); (K.M.); (T.B.)
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC—University Medical Center Rotterdam, 3015 CN Rotterdam, The Netherlands; (V.T.J.); (M.P.P.)
| | - Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland; (E.K.); (M.W.); (D.W.); (M.S.); (K.M.); (T.B.)
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Chen M, Ye AX, Wei J, Wang R, Poon K. Deoxycholic Acid Upregulates the Reprogramming Factors KFL4 and OCT4 Through the IL-6/STAT3 Pathway in Esophageal Adenocarcinoma Cells. Technol Cancer Res Treat 2020; 19:1533033820945302. [PMID: 32869704 PMCID: PMC7469721 DOI: 10.1177/1533033820945302] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Cancer stem cells, a special subgroup of cancer cells, have self-renewal capabilities and multidirectional potential, which may be reprogrammed from the dedifferentiation of cancer cells, contributing to the failure of clinical treatments. Esophageal adenocarcinoma grows in an inflammatory environment stimulated by deoxycholic acid, an important component of gastroesophageal reflux content, contributing to the transformation of esophageal squamous epithelium to the precancerous lesions of esophageal adenocarcinoma, that is, Barrett esophagus. In the present study, deoxycholic acid was used to investigate whether it could induce the expression of reprogramming factors Krüppel-like factor, OCT4, and Nanog; the transformation to cancer stem cells in esophageal adenocarcinoma; and the involvement of the interleukin-6/signal transduction and activation of transcription 3 inflammatory signaling pathway. OE33 cells were treated with deoxycholic acid (250 μM) for 0 hour, 3 hours, 6 hours, and 12 hours before evaluating the messenger RNA expression of Krüppel-like factor, OCT4, Nanog, interleukin-6, and Bcl-xL by reverse transcription-quantitative polymerase chain reaction. Interleukin-6 protein was detected by enzyme linked immunosorbent assay, while signal transduction and activation of transcription 3, phosphorylated signal transduction and activation of transcription 3, Krüppel-like factor, and OCT4 were detected by Western blot. Signal transduction and activation of transcription 3 small interfering RNA and human recombinant interleukin-6 were used to treat OE33 cells and to detect their effects on Krüppel-like factor, OCT4, Nanog, CD44, hypoxia-inducible factor 1-α, and Bcl-xL expression. Results showed that deoxycholic acid promotes the expression of reprogramming factors Krüppel-like factor and OCT4, which are regulated by the interleukin-6/signal transduction and activation of transcription 3 signaling pathway. Deoxycholic acid has a malignancy-inducing effect on the transformation of esophageal adenocarcinoma stem cells, improving the antiapoptotic ability of tumors, and increasing the malignancy of esophageal adenocarcinoma. Deactivating the regulatory signaling pathway of interleukin-6/signal transduction and activation of transcription 3 and neutralizing deoxycholic acid may be novel targets for improving the clinical efficacy of esophageal adenocarcinoma therapy.
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Affiliation(s)
- Mei Chen
- Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen, People's Republic of China
| | - AXiaojun Ye
- Division of Science and Technology, Program of Food Science and Technology, 125809BNU-HKBU United International College, Tangjiawan, Zhuhai, Guangdong, People's Republic of China
| | - Jingxi Wei
- Division of Science and Technology, Program of Food Science and Technology, 125809BNU-HKBU United International College, Tangjiawan, Zhuhai, Guangdong, People's Republic of China
| | - Ruihua Wang
- Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen, People's Republic of China
| | - Karen Poon
- Division of Science and Technology, Program of Food Science and Technology, 125809BNU-HKBU United International College, Tangjiawan, Zhuhai, Guangdong, People's Republic of China
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43
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Zhao A, Wang S, Chen W, Zheng X, Huang F, Han X, Ge K, Rajani C, Huang Y, Yu H, Zhu J, Jia W. Increased levels of conjugated bile acids are associated with human bile reflux gastritis. Sci Rep 2020; 10:11601. [PMID: 32665615 PMCID: PMC7360626 DOI: 10.1038/s41598-020-68393-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 05/07/2020] [Indexed: 01/07/2023] Open
Abstract
Bile acids (BAs) play essential roles in facilitating lipid digestion and absorption in the intestine. Gastric BAs were attributed to abnormal refluxing from duodenal compartments and correlated with the occurrence of gastric inflammation and carcinogenesis. However, the differences in gastric BAs between physiologically compromised and healthy individuals have not been fully investigated. In this study, gastric juice was collected from patients clinically diagnosed as gastritis with/without bile reflux and healthy subjects for BA profiles measurements. As a result, we found that the conjugated BAs became prominent components in bile reflux juice, whereas almost equal amounts of conjugated and unconjugated BAs existed in non-bile reflux and healthy juice. To investigate whether gastric BA changes were regulated by hepatic BA synthesis, C57BL/6J mice were intervened with GW4064/resin to decrease/increase hepatic BA synthesis. The results revealed that changes of gastric BAs were coordinated with hepatic BA changes. Additionally, gastric BAs were detected in several healthy mammals, in which there were no obvious differences between the conjugated and unconjugated BAs. Pigs were an exception. Thus, increased levels of conjugated BAs are associated with human bile reflux gastritis. Gastric conjugated BAs could become a panel of biomarkers to facilitate diagnosis of pathological bile reflux.
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Affiliation(s)
- Aihua Zhao
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Shouli Wang
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Wenlian Chen
- University of Hawaii Cancer Center, Honolulu, 96813, USA
| | - Xiaojiao Zheng
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Fengjie Huang
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Xiaolong Han
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Kun Ge
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Cynthia Rajani
- University of Hawaii Cancer Center, Honolulu, 96813, USA
| | - Yanxia Huang
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Herbert Yu
- University of Hawaii Cancer Center, Honolulu, 96813, USA
| | - Jinshui Zhu
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Wei Jia
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. .,University of Hawaii Cancer Center, Honolulu, 96813, USA.
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Vaezi MF, Fass R, Vakil N, Reasner DS, Mittleman RS, Hall M, Shao JZ, Chen Y, Lane L, Gates AM, Currie MG. IW-3718 Reduces Heartburn Severity in Patients With Refractory Gastroesophageal Reflux Disease in a Randomized Trial. Gastroenterology 2020; 158:2093-2103. [PMID: 32092310 DOI: 10.1053/j.gastro.2020.02.031] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 02/07/2020] [Accepted: 02/14/2020] [Indexed: 01/18/2023]
Abstract
BACKGROUND & AIMS Refractory gastroesophageal reflux disease (GERD) reduces quality of life and creates significant financial burden on the health care system. Approximately 30% of patients with GERD who receive label-dose proton pump inhibitors (PPIs) still have symptoms. We performed a trial to evaluate the efficacy and safety of IW-3718, a bile acid sequestrant, as an adjunct to PPI therapy. METHODS We performed a multicenter, double-blind, placebo-controlled trial, from March 2016 through April 2017, of 280 patients with confirmed GERD. The patients, stratified by esophagitis status, were randomly assigned (1:1:1:1) to groups given placebo or IW-3718 (500, 1000, or 1500 mg) twice daily, with ongoing label-dose PPI. The primary endpoint was percent change from baseline to week 8 in weekly heartburn severity score. We also analyzed percent change from baseline to week 8 in weekly regurgitation frequency score. RESULTS Mean changes from baseline to week 8 in weekly heartburn severity scores were reductions of 46.0% in the placebo group, 49.0% in the 500 mg group, 55.1% in the 1000 mg group, and 58.0% in the 1500 mg IW-3718 group (dose-response P = .02). The treatment difference was 11.9% between the 1500 mg IW-3718 and placebo groups (P = .04, analysis of covariance). The mean change in weekly regurgitation frequency score from baseline to week 8 in the 1500 mg IW-3718 vs placebo groups was a reduction of 17.5% (95% confidence interval, reductions of 31.4% to 3.6%). The most common adverse event was constipation (in 8.1% of patients receiving IW-3718 and 7.1% of patients receiving placebo). There were no drug-related serious adverse events. CONCLUSIONS In a randomized trial of patients with refractory GERD, adding 1500 mg IW-3718 to label-dose PPIs significantly reduced heartburn symptoms compared with adding placebo. Regurgitation symptoms also decreased. IW-3718 was well tolerated. (ClinicalTrials.gov, Number: NCT02637557).
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Affiliation(s)
| | - Ronnie Fass
- MetroHealth Medical Center and Case Western Reserve University, Cleveland, Ohio
| | - Nimish Vakil
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | | | | | - Michael Hall
- Ironwood Pharmaceuticals, Inc, Boston, Massachusetts
| | - James Z Shao
- Ironwood Pharmaceuticals, Inc, Boston, Massachusetts
| | - Yan Chen
- Ironwood Pharmaceuticals, Inc, Boston, Massachusetts
| | - Lara Lane
- Ironwood Pharmaceuticals, Inc, Boston, Massachusetts
| | - Amy M Gates
- Ironwood Pharmaceuticals, Inc, Boston, Massachusetts
| | - Mark G Currie
- Ironwood Pharmaceuticals, Inc, Boston, Massachusetts
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Zhang CYK, Ahmed M, Huszti E, Levy L, Hunter SE, Boonstra KM, Moshkelgosha S, Sage AT, Azad S, Zamel R, Ghany R, Yeung JC, Crespin OM, Frankel C, Budev M, Shah P, Reynolds JM, Snyder LD, Belperio JA, Singer LG, Weigt SS, Todd JL, Palmer SM, Keshavjee S, Martinu T. Bronchoalveolar bile acid and inflammatory markers to identify high-risk lung transplant recipients with reflux and microaspiration. J Heart Lung Transplant 2020; 39:934-944. [PMID: 32487471 DOI: 10.1016/j.healun.2020.05.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 04/20/2020] [Accepted: 05/11/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Gastroesophageal reflux disease (GERD) is a risk factor for chronic lung allograft dysfunction. Bile acids-putative markers of gastric microaspiration-and inflammatory proteins in the bronchoalveolar lavage (BAL) have been associated with chronic lung allograft dysfunction, but their relationship with GERD remains unclear. Although GERD is thought to drive chronic microaspiration, the selection of patients for anti-reflux surgery lacks precision. This multicenter study aimed to test the association of BAL bile acids with GERD, lung inflammation, allograft function, and anti-reflux surgery. METHODS We analyzed BAL obtained during the first post-transplant year from a retrospective cohort of patients with and without GERD, as well as BAL obtained before and after Nissen fundoplication anti-reflux surgery from a separate cohort. Levels of taurocholic acid (TCA), glycocholic acid, and cholic acid were measured using mass spectrometry. Protein markers of inflammation and injury were measured using multiplex assay and enzyme-linked immunosorbent assay. RESULTS At 3 months after transplantation, TCA, IL-1β, IL-12p70, and CCL5 were higher in the BAL of patients with GERD than in that of no-GERD controls. Elevated TCA and glycocholic acid were associated with concurrent acute lung allograft dysfunction and inflammatory proteins. The BAL obtained after anti-reflux surgery contained reduced TCA and inflammatory proteins compared with that obtained before anti-reflux surgery. CONCLUSIONS Targeted monitoring of TCA and selected inflammatory proteins may be useful in lung transplant recipients with suspected reflux and microaspiration to support diagnosis and guide therapy. Patients with elevated biomarker levels may benefit most from anti-reflux surgery to reduce microaspiration and allograft inflammation.
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Affiliation(s)
- Chen Yang Kevin Zhang
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Musawir Ahmed
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Ella Huszti
- Biostatistics Research Unit, University Health Network, Toronto, Ontario, Canada
| | - Liran Levy
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Sarah E Hunter
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Kristen M Boonstra
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Sajad Moshkelgosha
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Andrew T Sage
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Sassan Azad
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Ricardo Zamel
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Rasheed Ghany
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Jonathan C Yeung
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Oscar M Crespin
- Division of General Surgery, University Health Network, University of Toronto, Toronto, Canada
| | | | | | - Pali Shah
- Johns Hopkins University Hospital, Baltimore, Maryland
| | | | | | | | - Lianne G Singer
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | | | - Jamie L Todd
- Duke University Medical Center, Durham, North Carolina
| | | | - Shaf Keshavjee
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Tereza Martinu
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada.
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The Progressive Mutagenic Effects of Acidic Bile Refluxate in Hypopharyngeal Squamous Cell Carcinogenesis: New Insights. Cancers (Basel) 2020; 12:cancers12051064. [PMID: 32344873 PMCID: PMC7281001 DOI: 10.3390/cancers12051064] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 04/21/2020] [Accepted: 04/22/2020] [Indexed: 12/16/2022] Open
Abstract
Cancers of the laryngopharynx represent the most devastating of the head and neck malignancies and additional risk factors are now epidemiologically linked to this disease. Using an in vivo model (Mus musculus C57Bl/6J), we provide novel evidence that acidic bile (pH 3.0) progressively promotes invasive cancer in the hypopharynx. Malignant lesions are characterized by increasing: i) oxidative DNA-damage, ii) γH2AX expression, iii) NF-κB activation, and iv) p53 expression. Histopathological changes observed in murine hypopharyngeal mucosa exposed to acidic bile were preceded by the overexpression of Tnf, Il6, Bcl2, Egfr, Rela, Stat3, and the deregulation of miR-21, miR-155, miR-192, miR-34a, miR-375, and miR-451a. This is the first study to document that acidic bile is carcinogenic in the upper aerodigestive tract. We showed that oxidative DNA-damage produced by acidic bile in combination with NF-κB-related anti-apoptotic deregulation further supports the underlying two-hit hypothesized mechanism. Just as importantly, we reproduced the role of several biomarkers of progression that served as valuable indicators of early neoplasia in our experimental model. These findings provide a sound basis for proposing translational studies in humans by exposing new opportunities for early detection and prevention.
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Majka J, Wierdak M, Szlachcic A, Magierowski M, Targosz A, Urbanczyk K, Krzysiek-Maczka G, Ptak-Belowska A, Bakalarz D, Magierowska K, Chmura A, Brzozowski T. Interaction of epidermal growth factor with COX-2 products and peroxisome proliferator-activated receptor-γ system in experimental rat Barrett's esophagus. Am J Physiol Gastrointest Liver Physiol 2020; 318:G375-G389. [PMID: 31928220 DOI: 10.1152/ajpgi.00410.2018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
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 PGE2 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.
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Affiliation(s)
- Jolanta Majka
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Mateusz Wierdak
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Aleksandra Szlachcic
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Marcin Magierowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Aneta Targosz
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Katarzyna Urbanczyk
- Department of Pathomorphology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Gracjana Krzysiek-Maczka
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Agata Ptak-Belowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Dominik Bakalarz
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Katarzyna Magierowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Anna Chmura
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
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Huo X, Dunbar KB, Zhang X, Zhang Q, Spechler SJ, Souza RF. In Barrett's epithelial cells, weakly acidic bile salt solutions cause oxidative DNA damage with response and repair mediated by p38. Am J Physiol Gastrointest Liver Physiol 2020; 318:G464-G478. [PMID: 31984785 PMCID: PMC7099494 DOI: 10.1152/ajpgi.00329.2019] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/10/2020] [Accepted: 01/13/2020] [Indexed: 01/31/2023]
Abstract
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.
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Affiliation(s)
- Xiaofang Huo
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas
| | - Kerry B Dunbar
- Department of Medicine, Esophageal Diseases Center, Veterans Affairs North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas
| | - Xi Zhang
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas
| | - Qiuyang Zhang
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas
| | - Stuart Jon Spechler
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas
| | - Rhonda F Souza
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas
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Esophageal Adenocarcinoma After Antireflux Surgery in a Cohort Study From the 5 Nordic Countries. Ann Surg 2019; 274:e535-e540. [DOI: 10.1097/sla.0000000000003709] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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50
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Maret-Ouda J, Wahlin K, Artama M, Brusselaers N, Färkkilä M, Lynge E, Mattsson F, Pukkala E, Romundstad P, Tryggvadóttir L, von Euler-Chelpin M, Lagergren J. Risk of Esophageal Adenocarcinoma After Antireflux Surgery in Patients With Gastroesophageal Reflux Disease in the Nordic Countries. JAMA Oncol 2019; 4:1576-1582. [PMID: 30422249 DOI: 10.1001/jamaoncol.2018.3054] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Importance Gastroesophageal reflux disease (GERD) is associated with a strong and severity-dependent increased risk of esophageal adenocarcinoma. Whether antireflux surgery prevents esophageal adenocarcinoma is a matter of uncertainty. Objectives To examine whether antireflux surgery is associated with reduced risk of esophageal adenocarcinoma and whether the risk is different between surgically and medically treated patients. Design, Setting, and Participants In this multinational, population-based retrospective cohort study from Denmark, Finland, Iceland, Norway, and Sweden, patients undergoing surgery were followed up for a median of 12.7 years, and a comparison group of patients receiving medication only were followed up for a median of 4.8 years. All patients with a registered diagnosis of GERD (or an associated disorder), including 48 414 individuals undergoing surgery and 894 492 receiving medication only, were included in the study. The study periods varied in the different countries depending on the year of initiation of registration and the date of data retrieval, from January 1, 1964, to December 21, 2014. Exposures Antireflux surgery for GERD. Main Outcomes and Measures The risk of esophageal adenocarcinoma over time after surgery was compared with that in a corresponding background population using standardized incidence ratios (SIRs) with 95% CIs and with patients with GERD who received medication using multivariable Cox proportional hazards regression, providing hazard ratios (HRs) with 95% CIs adjusted for confounders. Results In this study of 942 906 patients with GERD, 48 414 underwent antireflux surgery (median [interquartile range] age, 66.0 [58.0-73.0] years; 27 161 male [56.1%]) and 894 492 received medication only (median [interquartile range] age, 71.0 [62.0-78.0] years; 434 035 male [48.6%]). Among patients undergoing surgery, 177 developed esophageal adenocarcinoma. Esophageal adenocarcinoma risk decreased in a time-dependent manner after surgery compared with the background population (5 to <10 years after surgery: SIR, 7.63; 95% CI, 5.42-10.43; ≥15 years after surgery: SIR, 1.34; 95% CI, 0.98-1.80). Among patients with more severe and objectively determined GERD, the SIRs were 10.08 (95% CI, 6.98-14.09) at 5 to less than 10 years after surgery and 1.67 (95% CI, 1.15-2.35) at 15 years or more after surgery. The risk of esophageal adenocarcinoma did not change over time in surgical patients compared with patients who received medication only (5 to <10 years after surgery: HR, 2.02; 95% CI, 1.44-2.84; ≥15 years: HR, 1.80; 95% CI, 1.28-2.54). The risk remained stable over time in analyses restricted to severe reflux disease (5 to <10 years after surgery: HR, 1.81; 95% CI, 1.24-2.63; ≥15 years after surgery: HR, 1.69; 95% CI, 1.14-2.51). Conclusions and Relevance Medical and surgical treatment of GERD were associated with a similar reduced esophageal adenocarcinoma risk, with the risk decreasing to the same level as that in the background population over time, supporting the hypothesis that effective treatment of GERD might prevent esophageal adenocarcinoma.
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Affiliation(s)
- John Maret-Ouda
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Karl Wahlin
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Miia Artama
- Impact Assessment Unit, Department of Health Protection, National Institute for Health and Welfare, Tampere, Finland
| | - Nele Brusselaers
- Centre for Translational Microbiome Research, Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden.,Science For Life Laboratory (SciLifeLab), Karolinska Institutet, Stockholm, Sweden
| | - Martti Färkkilä
- Clinic of Gastroenterology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Elsebeth Lynge
- Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Fredrik Mattsson
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Eero Pukkala
- Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.,Faculty of Social Sciences, University of Tampere, Tampere, Finland
| | - Pål Romundstad
- Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Laufey Tryggvadóttir
- Icelandic Cancer Registry, Icelandic Cancer Society, Reykjavik, Iceland.,Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | | | - Jesper Lagergren
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,School of Cancer Sciences, King's College London, London, United Kingdom
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