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Regulation and Treatment of Esophageal Mucosa Disorders: Novel Factors, Mechanisms, and Pharmaceutical Targets

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 11141

Special Issue Editors

Dr. Marcin Magierowski

E-Mail Website
Guest Editor
Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
Interests: gaseous mediators; hydrogen sulfide; carbon monoxide; molecular gastroenterology; gastrointestinal pharmacology; Barrett’s esophagus; digestive system pathologies
Special Issues, Collections and Topics in MDPI journals
Dr. Rhonda F. Souza

E-Mail Website
Guest Editor
Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott &White Research Institute, Dallas, TX 75246, USA
Interests: gastroesophageal reflux disease; Barrett’s esophagus; esophageal adenocarcinoma; eosinophilic esophagitis; achalasia; digestive system pathologies

Special Issue Information

Dear Colleagues, 

Esophageal epithelium-related pathologies, among others including gastroesophageal reflux disease (GERD)-associated diseases such as Barrett’s esophagus (BE) or esophageal adenocarcinoma (EAC), are key clinical problems. For instance, GERD symptoms are assumed to affect 10–20% of the population, while BE is a premalignant condition progressing to EAC with a very high mortality rate. Thus, several translational experimental models have been developed to reflect the clinical course of Barrett's metaplasia progression. However, the pathogenesis of esophageal epithelium pathologies involves a complex molecular mechanism which is still to be fully defined.

This Special Issue is open to original and review articles targeting molecular aspects of esophageal epithelium disease development and progression. Clinical submissions but with biomolecular experiments are welcomed. We also encourage you to submit the manuscripts covering possible pharmacological targets for upper gastrointestinal tract pathologies’ treatment and prevention. 

Dr. Marcin Magierowski
Dr. Rhonda F. Souza
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • esophageal epithelium
  • Barrett’s esophagus
  • esophageal adenocarcinoma
  • gastroesophageal reflux disease
  • gastrointestinal pharmacology
  • gastrointestinal molecular pathology

Published Papers (5 papers)

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Research

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21 pages, 5367 KiB  
Article
Augmented CPT1A Expression Is Associated with Proliferation and Colony Formation during Barrett’s Tumorigenesis
by Joshua N. Bernard, Vikram Chinnaiyan, Thomas Andl, Gregoire F. Le Bras, M. Nasar Qureshi, Deborah A. Altomare and Claudia D. Andl
Int. J. Mol. Sci. 2022, 23(19), 11745; https://doi.org/10.3390/ijms231911745 - 4 Oct 2022
Cited by 2 | Viewed by 2055
Abstract
Obesity is a known risk factor for the development of gastroesophageal reflux disease (GERD), Barrett’s Esophagus (BE) and the progression to esophageal adenocarcinoma. The mechanisms by which obesity contributes to GERD, BE and its progression are currently not well understood. Recently, changes in [...] Read more.
Obesity is a known risk factor for the development of gastroesophageal reflux disease (GERD), Barrett’s Esophagus (BE) and the progression to esophageal adenocarcinoma. The mechanisms by which obesity contributes to GERD, BE and its progression are currently not well understood. Recently, changes in lipid metabolism especially in the context of a high fat diet have been linked to GERD and BE leading us to explore whether fatty acid oxidation plays a role in the disease progression from GERD to esophageal adenocarcinoma. To that end, we analyzed the expression of the rate-limiting enzyme, carnitine palmytoyltransferase 1A (CPT1A), in human tissues and cell lines representing different stages in the sequence from normal squamous esophagus to cancer. We determined uptake of palmitic acid, the most abundant fatty acid in human serum, with fluorescent dye-labeled lipids as well as functional consequences of stimulation with palmitic acid relevant to Barrett’s tumorigenesis, e.g., proliferation, characteristics of stemness and IL8 mediated inflammatory signaling. We further employed different mouse models including a genetic model of Barrett’s esophagus based on IL1β overexpression in the presence and absence of a high fat diet and deoxycholic acid to physiologically mimic gastrointestinal reflux in the mice. Together, our data demonstrate that CPT1A is upregulated in Barrett’s tumorigenesis and that experimental palmitic acid is delivered to mitochondria and associated with increased cell proliferation and stem cell marker expression. Full article
(This article belongs to the Special Issue Regulation and Treatment of Esophageal Mucosa Disorders: Novel Factors, Mechanisms, and Pharmaceutical Targets)
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22 pages, 5250 KiB  
Article
Inflammatory and Proliferative Pathway Activation in Human Esophageal Myofibroblasts Treated with Acidic Bile Salts
by Madhura Patankar, Meng Li, Atousa Khalatbari, Joshua D. Castle, Liping Hu, Chunying Zhang and Anisa Shaker
Int. J. Mol. Sci. 2022, 23(18), 10371; https://doi.org/10.3390/ijms231810371 - 8 Sep 2022
Cited by 6 | Viewed by 2053
Abstract
Subepithelial human esophageal myofibroblasts (HEMFs) in gastroesophageal reflux disease (GERD) are exposed to luminal contents via impaired squamous epithelium barrier integrity. The supernatant of HEMFs treated with acidic bile salts reflective of in vivo reflux increases squamous epithelial thickness. We aimed to identify [...] Read more.
Subepithelial human esophageal myofibroblasts (HEMFs) in gastroesophageal reflux disease (GERD) are exposed to luminal contents via impaired squamous epithelium barrier integrity. The supernatant of HEMFs treated with acidic bile salts reflective of in vivo reflux increases squamous epithelial thickness. We aimed to identify the involved mechanisms using an unbiased approach. Acidic-bile-salt-treated primary HEMF cultures (n = 4) were submitted for RNA-Seq and analyzed with Partek Flow followed by Ingenuity Pathway Analysis (IPA). A total of 1165 molecules (579 downregulated, 586 upregulated) were differentially expressed, with most top regulated molecules either extracellular or in the plasma membrane. Increases in HEMF CXCL-8, IL-6, AREG, and EREG mRNA, and protein secretion were confirmed. Top identified canonical pathways were agranulocyte and granulocyte adhesion and diapedesis, PI3K/AKT signaling, CCR5 signaling in macrophages, and the STAT3 pathway. Top diseases and biological functions were cellular growth and development, hematopoiesis, immune cell trafficking, and cell-mediated response. The targets of the top upstream regulator ErbB2 included CXCL-8, IL-6, and AREG and the inhibition of CXCL-8 in the HEMF supernatant decreased squamous epithelial proliferation. Our work shows an inflammatory/immune cell and proliferative pathways activation in HEMFs in the GERD environment and identifies CXCL-8 as a HEMF-derived chemokine with paracrine proliferative effects on squamous epithelium. Full article
(This article belongs to the Special Issue Regulation and Treatment of Esophageal Mucosa Disorders: Novel Factors, Mechanisms, and Pharmaceutical Targets)
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24 pages, 1924 KiB  
Article
Barrett’s Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models
by Edyta Korbut, Kinga Krukowska and Marcin Magierowski
Int. J. Mol. Sci. 2022, 23(6), 3312; https://doi.org/10.3390/ijms23063312 - 18 Mar 2022
Viewed by 2507
Abstract
The molecular processes that predispose the development of Barrett’s esophagus (BE) towards esophageal adenocarcinoma (EAC) induced by gastrointestinal reflux disease (GERD) are still under investigation. In this study, based on a scientific literature screening and an analysis of clinical datasets, we selected a [...] Read more.
The molecular processes that predispose the development of Barrett’s esophagus (BE) towards esophageal adenocarcinoma (EAC) induced by gastrointestinal reflux disease (GERD) are still under investigation. In this study, based on a scientific literature screening and an analysis of clinical datasets, we selected a panel of 20 genes covering BE- and EAC-specific molecular markers (FZD5, IFNGR1, IL1A, IL1B, IL1R1, IL1RN, KRT4, KRT8, KRT15, KRT18, NFKBIL1, PTGS1, PTGS2, SOCS3, SOX4, SOX9, SOX15, TIMP1, TMEM2, TNFRSF10B). Furthermore, we aimed to reflect these alterations within an experimental and translational in vitro model of BE to EAC progression. We performed a comparison between expression profiles in GSE clinical databases with an in vitro model of GERD involving a BE cell line (BAR-T) and EAC cell lines (OE33 and OE19). Molecular responses of cells treated with acidified bile mixture (BM) at concentration of 100 and 250 μM for 30 min per day were evaluated. We also determined a basal mRNA expression within untreated, wild type cell lines on subsequent stages of BE and EAC development. We observed that an appropriately optimized in vitro model based on the combination of BAR-T, OE33 and OE19 cell lines reflects in 65% and more the clinical molecular alterations observed during BE and EAC development. We also confirmed previous observations that exposure to BM (GERD in vitro) activated carcinogenesis in non-dysplastic cells, inducing molecular alternations in the advanced stages of BE. We conclude that it is possible to induce, to a high extent, the molecular profile observed clinically within appropriately and carefully optimized experimental models, triggering EAC development. This experimental scheme and molecular marker panel might be implemented in further research, e.g., aiming to develop and evaluate novel compounds and prodrugs targeting GERD as well as BE and EAC prevention and treatment. Full article
(This article belongs to the Special Issue Regulation and Treatment of Esophageal Mucosa Disorders: Novel Factors, Mechanisms, and Pharmaceutical Targets)
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Review

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18 pages, 1618 KiB  
Review
Translating Molecular Biology Discoveries to Develop Targeted Cancer Interception in Barrett’s Esophagus
by Sohini Samaddar, Daniel Buckles, Souvik Saha, Qiuyang Zhang and Ajay Bansal
Int. J. Mol. Sci. 2023, 24(14), 11318; https://doi.org/10.3390/ijms241411318 - 11 Jul 2023
Viewed by 1655
Abstract
Esophageal adenocarcinoma (EAC) is a rapidly increasing lethal tumor. It commonly arises from a metaplastic segment known as Barrett’s esophagus (BE), which delineates the at-risk population. Ample research has elucidated the pathogenesis of BE and its progression from metaplasia to invasive carcinoma; and [...] Read more.
Esophageal adenocarcinoma (EAC) is a rapidly increasing lethal tumor. It commonly arises from a metaplastic segment known as Barrett’s esophagus (BE), which delineates the at-risk population. Ample research has elucidated the pathogenesis of BE and its progression from metaplasia to invasive carcinoma; and multiple molecular pathways have been implicated in this process, presenting several points of cancer interception. Here, we explore the mechanisms of action of various agents, including proton pump inhibitors, non-steroidal anti-inflammatory drugs, metformin, and statins, and explain their roles in cancer interception. Data from the recent AspECT trial are discussed to determine how viable a multipronged approach to cancer chemoprevention would be. Further, novel concepts, such as the repurposing of chemotherapeutic drugs like dasatinib and the prevention of post-ablation BE recurrence using itraconazole, are discussed. Full article
(This article belongs to the Special Issue Regulation and Treatment of Esophageal Mucosa Disorders: Novel Factors, Mechanisms, and Pharmaceutical Targets)
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12 pages, 603 KiB  
Review
Sensory Phenotype of the Oesophageal Mucosa in Gastro-Oesophageal Reflux Disease
by Ahsen Ustaoglu and Philip Woodland
Int. J. Mol. Sci. 2023, 24(3), 2502; https://doi.org/10.3390/ijms24032502 - 28 Jan 2023
Cited by 6 | Viewed by 1931
Abstract
Gastroesophageal reflux disease (GORD) affects up to 20% of Western populations, yet sensory mechanisms underlying heartburn pathogenesis remain incompletely understood. While central mechanisms of heartburn perception have been established in earlier studies, recent studies have highlighted an important role of neurochemical, inflammatory, and [...] Read more.
Gastroesophageal reflux disease (GORD) affects up to 20% of Western populations, yet sensory mechanisms underlying heartburn pathogenesis remain incompletely understood. While central mechanisms of heartburn perception have been established in earlier studies, recent studies have highlighted an important role of neurochemical, inflammatory, and cellular changes occurring in the oesophageal mucosa itself. The localization and neurochemical characterisation of sensory afferent nerve endings differ among GORD phenotypes, and could explain symptom heterogeneity among patients who are exposed to similar levels of reflux. Acid-induced stimulation of nociceptors on pain-sensing nerve endings can regulate afferent signal transmission. This review considers the role of peripheral mechanisms of sensitization in the amplification of oesophageal sensitivity in patients with GORD. Full article
(This article belongs to the Special Issue Regulation and Treatment of Esophageal Mucosa Disorders: Novel Factors, Mechanisms, and Pharmaceutical Targets)
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