Chronic Gastroesophageal Reflux Dysregulates Proteostasis in Esophageal Epithelial CellsSummary
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 tu...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X24001899 |
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| author | Kodisundaram Paulrasu Ravindran Caspa Gokulan Wael El-Rifai Zhibin Chen Jianwen Que Timothy C. Wang Olivier G. Boutaud Karoline Briegel Sergey I. Dikalov Monica T. Garcia-Buitrago Alexander I. Zaika |
| author_facet | Kodisundaram Paulrasu Ravindran Caspa Gokulan Wael El-Rifai Zhibin Chen Jianwen Que Timothy C. Wang Olivier G. Boutaud Karoline Briegel Sergey I. Dikalov Monica T. Garcia-Buitrago Alexander I. Zaika |
| author_sort | Kodisundaram Paulrasu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f2e3121d6a484a25838121b52a7d5fd7 |
| institution | Kabale University |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-f2e3121d6a484a25838121b52a7d5fd72025-01-18T05:04:47ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-01193101434Chronic Gastroesophageal Reflux Dysregulates Proteostasis in Esophageal Epithelial CellsSummaryKodisundaram Paulrasu0Ravindran Caspa Gokulan1Wael El-Rifai2Zhibin Chen3Jianwen Que4Timothy C. Wang5Olivier G. Boutaud6Karoline Briegel7Sergey I. Dikalov8Monica T. Garcia-Buitrago9Alexander I. Zaika10Department of Surgery, University of Miami, Miami, FloridaDepartment of Surgery, University of Miami, Miami, Florida; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FloridaDepartment of Surgery, University of Miami, Miami, FloridaDepartment of Microbiology and Immunology, University of Miami, Miami, FloridaDepartment of Medicine, Columbia University Medical Center, New York, New YorkDepartment of Medicine, Columbia University Medical Center, New York, New YorkDepartment of Pharmacology, Vanderbilt University, Nashville, TennesseeDepartment of Surgery, University of Miami, Miami, FloridaDivision of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TennesseeDepartment of Clinical Pathology, University of Miami, Miami, FloridaDepartment 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; Correspondence Address correspondence to: Alexander I. Zaika, Department of Surgery, University of Miami, Miller School of Medicine, 1600 NW 10th Avenue, RMSB 4116, Miami, Florida 33136.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.http://www.sciencedirect.com/science/article/pii/S2352345X24001899GERDProteostasisOxidative StressLipid Peroxidation |
| spellingShingle | Kodisundaram Paulrasu Ravindran Caspa Gokulan Wael El-Rifai Zhibin Chen Jianwen Que Timothy C. Wang Olivier G. Boutaud Karoline Briegel Sergey I. Dikalov Monica T. Garcia-Buitrago Alexander I. Zaika Chronic Gastroesophageal Reflux Dysregulates Proteostasis in Esophageal Epithelial CellsSummary Cellular and Molecular Gastroenterology and Hepatology GERD Proteostasis Oxidative Stress Lipid Peroxidation |
| title | Chronic Gastroesophageal Reflux Dysregulates Proteostasis in Esophageal Epithelial CellsSummary |
| title_full | Chronic Gastroesophageal Reflux Dysregulates Proteostasis in Esophageal Epithelial CellsSummary |
| title_fullStr | Chronic Gastroesophageal Reflux Dysregulates Proteostasis in Esophageal Epithelial CellsSummary |
| title_full_unstemmed | Chronic Gastroesophageal Reflux Dysregulates Proteostasis in Esophageal Epithelial CellsSummary |
| title_short | Chronic Gastroesophageal Reflux Dysregulates Proteostasis in Esophageal Epithelial CellsSummary |
| title_sort | chronic gastroesophageal reflux dysregulates proteostasis in esophageal epithelial cellssummary |
| topic | GERD Proteostasis Oxidative Stress Lipid Peroxidation |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X24001899 |
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