{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:23Z","timestamp":1787028563802,"version":"build-2736575974"},"reference-count":119,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wisconsin Department of Otolaryngology and Communication Sciences"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gastroesophageal reflux disease (GERD) is associated with inflammatory and neoplastic changes in the esophageal epithelium. Despite widespread PPI use, esophageal adenocarcinoma (EAC) incidence continues to rise, implicating non-acidic reflux components such as pepsin in disease progression. We performed transcriptomic profiling to assess pepsin-induced changes and the protective effect of amprenavir in vitro. Het-1A (normal) and BAR-T (Barrett\u2019s) cells (n = 3) were treated at pH 7.0 with pepsin and\/or 10 \u03bcM amprenavir for 1 h. RNA-seq identified DEGs (FDR \u2264 0.05, |log\u2082FC| \u2265 0.375), and Ingenuity Pathway Analysis revealed enriched pathways. Pepsin exposure altered mitochondrial function, oxidative phosphorylation, epithelial integrity, signaling, and inflammatory pathways in both cell lines. Amprenavir attenuated these transcriptomic perturbations, preserving mitochondrial and stress-response pathways. Notably, BAR-T cells exhibited heightened activation of wound-healing and epithelial repair pathways, whereas Het-1A cells showed greater mitochondrial and systemic stress pathway alterations. Pepsin drives transcriptomic dysregulation in esophageal epithelial cells under non-acidic conditions, and amprenavir shows potential to counteract peptic injury. Further studies are needed to validate these findings and explore amprenavir\u2019s therapeutic utility in GERD management and EAC prevention.<\/jats:p>","DOI":"10.3390\/ijms26136182","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T03:33:25Z","timestamp":1750995205000},"page":"6182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Amprenavir Mitigates Pepsin-Induced Transcriptomic Changes in Normal and Precancerous Esophageal Cells"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3155-0633","authenticated-orcid":false,"given":"Pelin","family":"Ergun","sequence":"first","affiliation":[{"name":"Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7045-357X","authenticated-orcid":false,"given":"Tina L.","family":"Samuels","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6763-2710","authenticated-orcid":false,"given":"Angela J.","family":"Mathison","sequence":"additional","affiliation":[{"name":"Mellowes Center for Genomic Science and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianxiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, Data Science Institute, MCW Cancer Center and Mellowes Center for Genome Science and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8765-3471","authenticated-orcid":false,"given":"Victor X.","family":"Jin","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, Data Science Institute, MCW Cancer Center and Mellowes Center for Genome Science and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikki","family":"Johnston","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"436","DOI":"10.5056\/jnm22142","article-title":"Revisiting the Role of Esophageal Mucosal Dilated Intercellular Spaces in the Diagnosis and Pathophysiology of Heartburn","volume":"29","author":"Gorgulu","year":"2023","journal-title":"J. Neurogastroenterol. Motil."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e14075","DOI":"10.1111\/nmo.14075","article-title":"ESNM\/ANMS consensus paper: Diagnosis and management of refractory gastro-esophageal reflux disease","volume":"33","author":"Zerbib","year":"2021","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Nirwan, J.S., Hasan, S.S., Babar, Z.U., Conway, B.R., and Ghori, M.U. (2020). Global Prevalence and Risk Factors of Gastro-oesophageal Reflux Disease (GORD): Systematic Review with Meta-analysis. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-62795-1"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/j.cgh.2022.01.025","article-title":"AGA Clinical Practice Update on the Personalized Approach to the Evaluation and Management of GERD: Expert Review","volume":"20","author":"Yadlapati","year":"2022","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/s41572-021-00287-w","article-title":"Gastro-oesophageal reflux disease","volume":"7","author":"Fass","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ergun, P., Kipcak, S., and Bor, S. (2023). Epigenetic Alterations from Barrett\u2019s Esophagus to Esophageal Adenocarcinoma. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24097817"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Fossmark, R., Martinsen, T.C., and Waldum, H.L. (2019). Adverse Effects of Proton Pump Inhibitors-Evidence and Plausibility. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205203"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17","DOI":"10.5056\/jnm23145","article-title":"Refractory Gastroesophageal Reflux Disease: Diagnosis and Management","volume":"30","author":"Davis","year":"2024","journal-title":"J. Neurogastroenterol. Motil."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ergun, P., Kipcak, S., Gorgulu, V., Doganavsargil, B., and Bor, S. (2025). Molecular and Functional Recovery of Esophageal Barrier Integrity After Laparoscopic Anti-reflux Surgery. Dig. Dis. Sci.","DOI":"10.1007\/s10620-025-08951-x"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1016\/j.cgh.2020.03.057","article-title":"Untangling Nonerosive Reflux Disease From Functional Heartburn","volume":"19","author":"Patel","year":"2021","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1097\/MCG.0000000000001560","article-title":"Pepsin and pH of Gastric Juice in Patients With Gastrointestinal Reflux Disease and Subgroups","volume":"56","author":"Ergun","year":"2022","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"290","DOI":"10.5056\/jnm22186","article-title":"Roles of Cytokines in Pathological and Physiological Gastroesophageal Reflux Exposure","volume":"30","author":"Ergun","year":"2024","journal-title":"J. Neurogastroenterol. Motil."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"871","DOI":"10.4240\/wjgs.v16.i3.871","article-title":"Inflammatory responses in esophageal mucosa before and after laparoscopic antireflux surgery","volume":"16","author":"Ergun","year":"2024","journal-title":"World J. Gastrointest. Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1097\/MOO.0000000000000664","article-title":"Pepsin in gastroesophageal and extraesophageal reflux: Molecular pathophysiology and diagnostic utility","volume":"28","author":"Samuels","year":"2020","journal-title":"Curr. Opin. Otolaryngol. Head Neck Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1002\/lary.28051","article-title":"Esophageal pepsin and proton pump synthesis in barrett\u2019s esophagus and esophageal adenocarcinoma","volume":"129","author":"Samuels","year":"2019","journal-title":"Laryngoscope"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Han, D., and Zhang, C. (2022). The Oxidative Damage and Inflammation Mechanisms in GERD-Induced Barrett\u2019s Esophagus. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.885537"},{"key":"ref_17","first-page":"e12759","article-title":"Adverse Effects Associated with Proton Pump Inhibitor Use","volume":"13","author":"Yibirin","year":"2021","journal-title":"Cureus"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1136\/gutjnl-2019-318260","article-title":"How to select patients for antireflux surgery? The ICARUS guidelines (international consensus regarding preoperative examinations and clinical characteristics assessment to select adult patients for antireflux surgery)","volume":"68","author":"Pauwels","year":"2019","journal-title":"Gut"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1002\/lary.30242","article-title":"Oral and Inhaled Fosamprenavir Reverses Pepsin-Induced Damage in a Laryngopharyngeal Reflux Mouse Model","volume":"133","author":"Johnston","year":"2023","journal-title":"Laryngoscope"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1002\/prot.22271","article-title":"Interactions of different inhibitors with active-site aspartyl residues of HIV-1 protease and possible relevance to pepsin","volume":"75","author":"Sayer","year":"2009","journal-title":"Proteins"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1111\/nyas.13729","article-title":"Pepsin: Biomarker, mediator, and therapeutic target for reflux and aspiration","volume":"1434","author":"Johnston","year":"2018","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1177\/000348940711601211","article-title":"Receptor-mediated uptake of pepsin by laryngeal epithelial cells","volume":"116","author":"Johnston","year":"2007","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1177\/000348940911800913","article-title":"Pepsin in nonacidic refluxate can damage hypopharyngeal epithelial cells","volume":"118","author":"Johnston","year":"2009","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Blaine-Sauer, S., Samuels, T.L., Yan, K., and Johnston, N. (2023). The Protease Inhibitor Amprenavir Protects against Pepsin-Induced Esophageal Epithelial Barrier Disruption and Cancer-Associated Changes. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076765"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1002\/lio2.1102","article-title":"Amprenavir inhibits pepsin-mediated laryngeal epithelial disruption and E-cadherin cleavage in vitro","volume":"8","author":"Samuels","year":"2023","journal-title":"Laryngoscope Investig. Otolaryngol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ergun, P., Samuels, T.L., Mathison, A.J., Plehhova, K., Coyle, C., Horvath, L., and Johnston, N. (2024). Global Transcriptomic Analysis of Topical Sodium Alginate Protection against Peptic Damage in an In Vitro Model of Treatment-Resistant Gastroesophageal Reflux Disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910714"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Quilty, F., Freeley, M., Gargan, S., Gilmer, J., and Long, A. (2021). Deoxycholic acid induces proinflammatory cytokine production by model oesophageal cells via lipid rafts. J. Steroid Biochem. Mol. Biol., 214.","DOI":"10.1016\/j.jsbmb.2021.105987"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"G388","DOI":"10.1152\/ajpgi.90428.2008","article-title":"Effect of curcumin on acidic pH-induced expression of IL-6 and IL-8 in human esophageal epithelial cells (HET-1A): Role of PKC, MAPKs, and NF-kappaB","volume":"296","author":"Rafiee","year":"2009","journal-title":"Am. J. Physiol.-Gastrointest. Liver Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1111\/j.1442-2050.2007.00683.x","article-title":"Characterization of telomerase-immortalized, non-neoplastic, human Barrett\u2019s cell line (BAR-T)","volume":"20","author":"Jaiswal","year":"2007","journal-title":"Dis. Esophagus"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1177\/0003489415590657","article-title":"Local Synthesis of Pepsin in Barrett\u2019s Esophagus and the Role of Pepsin in Esophageal Adenocarcinoma","volume":"124","author":"Samuels","year":"2015","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s13402-012-0076-6","article-title":"Cell culture models for studying the development of Barrett\u2019s esophagus: A systematic review","volume":"35","author":"Bus","year":"2012","journal-title":"Cell Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1111\/jgh.15879","article-title":"Long-term proton pump inhibitor use and risk of osteoporosis and hip fractures: A nationwide population-based and multicenter cohort study using a common data model","volume":"37","author":"Park","year":"2022","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lespessailles, E., and Toumi, H. (2022). Proton Pump Inhibitors and Bone Health: An Update Narrative Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810733"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ito, T., Ramos-Alvarez, I., and Jensen, R.T. (2024). Long-Term Proton Pump Inhibitor-Acid Suppressive Treatment Can Cause Vitamin B(12) Deficiency in Zollinger-Ellison Syndrome (ZES) Patients. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25137286"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Brusnic, O., Onisor, D., Boicean, A., Hasegan, A., Ichim, C., Guzun, A., Chicea, R., Todor, S.B., Vintila, B.I., and Anderco, P. (2024). Fecal Microbiota Transplantation: Insights into Colon Carcinogenesis and Immune Regulation. J. Clin. Med., 13.","DOI":"10.3390\/jcm13216578"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1056\/NEJMoa1811424","article-title":"Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn","volume":"381","author":"Spechler","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.mcna.2018.08.002","article-title":"Proton Pump Inhibitor-Refractory Gastroesophageal Reflux Disease","volume":"103","author":"Yadlapati","year":"2019","journal-title":"Med. Clin. North. Am."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1111\/jgh.16471","article-title":"The efficacy and safety of fexuprazan in treating erosive esophagitis: A phase III, randomized, double-blind, multicenter study","volume":"39","author":"Zhuang","year":"2024","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1053\/j.gastro.2022.09.041","article-title":"Vonoprazan Versus Lansoprazole for Healing and Maintenance of Healing of Erosive Esophagitis: A Randomized Trial","volume":"164","author":"Laine","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1111\/apt.12693","article-title":"Proton pump inhibitor use may not prevent high-grade dysplasia and oesophageal adenocarcinoma in Barrett\u2019s oesophagus: A nationwide study of 9883 patients","volume":"39","author":"Pedersen","year":"2014","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.21037\/tcr-20-3362","article-title":"Risk of esophageal adenocarcinoma in patients with Barrett\u2019s esophagus using proton pump inhibitors: A systematic review with meta-analysis and sequential trial analysis","volume":"10","author":"Li","year":"2021","journal-title":"Transl. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Hu, Q., Sun, T.T., Hong, J., Fang, J.Y., Xiong, H., and Meltzer, S.J. (2017). Proton Pump Inhibitors Do Not Reduce the Risk of Esophageal Adenocarcinoma in Patients with Barrett\u2019s Esophagus: A Systematic Review and Meta-Analysis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169691"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1053\/j.gastro.2019.03.072","article-title":"Pathogenesis and Cells of Origin of Barrett\u2019s Esophagus","volume":"157","author":"Que","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5210","DOI":"10.3748\/wjg.v21.i17.5210","article-title":"From reflux esophagitis to Barrett\u2019s esophagus and esophageal adenocarcinoma","volume":"21","author":"Wang","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1007\/s10517-021-05273-6","article-title":"Response of Esophageal Epithelium to Acute and Chronic Stress in Rabbits","volume":"171","author":"Capanoglu","year":"2021","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1177\/000348941011900808","article-title":"Rationale for targeting pepsin in the treatment of reflux disease","volume":"119","author":"Johnston","year":"2010","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"102681","DOI":"10.1016\/j.amjoto.2020.102681","article-title":"Association of pepsin and DNA damage in laryngopharyngeal reflux-related vocal fold polyps","volume":"41","author":"Dai","year":"2020","journal-title":"Am. J. Otolaryngol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3080","DOI":"10.1002\/lary.31239","article-title":"Pepsin Inhibitors Prevent Inflammation and Loss of Laryngeal Barrier Function in Mice with Gastroesophageal Reflux","volume":"134","author":"Sales","year":"2024","journal-title":"Laryngoscope"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/lary.28636","article-title":"RNA Sequencing Reveals Cancer-Associated Changes in Laryngeal Cells Exposed to Non-Acid Pepsin","volume":"131","author":"Samuels","year":"2021","journal-title":"Laryngoscope"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Hou, C., Zhou, L., Zheng, Y., Chen, T., Hu, R., Zheng, J., Liu, C., and Liu, Y. (2025). Weak acid and pepsin reflux induce laryngopharyngeal mucosal barrier injury: A rabbit-model-based study. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0315083"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1002\/alr.22685","article-title":"Pepsin exposure in a non-acidic environment upregulates mucin 5AC (MUC5AC) expression via matrix metalloproteinase 9 (MMP9)\/nuclear factor \u03baB (NF-\u03baB) in human airway epithelial cells","volume":"11","author":"Choi","year":"2021","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Doukas, P.G., Vageli, D.P., Sasaki, C.T., and Judson, B.L. (2021). Pepsin Promotes Activation of Epidermal Growth Factor Receptor and Downstream Oncogenic Pathways, at Slightly Acidic and Neutral pH, in Exposed Hypopharyngeal Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084275"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Sasaki, C.T., Toman, J., and Vageli, D. (2016). The In Vitro Effect of Acidic-Pepsin on Nuclear Factor KappaB Activation and Its Related Oncogenic Effect on Normal Human Hypopharyngeal Cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168269"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1002\/lary.20665","article-title":"Laryngeal mucosa: Its susceptibility to damage by acid and pepsin","volume":"120","author":"Bulmer","year":"2010","journal-title":"Laryngoscope"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1124\/mol.115.097857","article-title":"G Protein-Coupled Receptor and RhoA-Stimulated Transcriptional Responses: Links to Inflammation, Differentiation, and Cell Proliferation","volume":"88","author":"Yu","year":"2015","journal-title":"Mol. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1186\/s12943-020-01238-x","article-title":"Natural killer cells in cancer biology and therapy","volume":"19","author":"Wu","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Zhang, Y., and Fai, T.G. (2023). Influence of the vessel wall geometry on the wall-induced migration of red blood cells. PLoS Comput. Biol., 19.","DOI":"10.1371\/journal.pcbi.1011241"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/aps.2011.200","article-title":"Role of G protein-coupled receptors in inflammation","volume":"33","author":"Sun","year":"2012","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Gruden, E., Kienzl, M., Ristic, D., Kindler, O., Kaspret, D.M., Schmid, S.T., Kargl, J., Sturm, E., Doyle, A.D., and Wright, B.L. (2024). Mononuclear cell composition and activation in blood and mucosal tissue of eosinophilic esophagitis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1347259"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.2147\/JIR.S282809","article-title":"Laryngopharyngeal Reflux and Inflammatory Responses in Mucosal Barrier Dysfunction of the Upper Aerodigestive Tract","volume":"13","author":"Liu","year":"2020","journal-title":"J. Inflamm. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1186\/s12967-024-05549-1","article-title":"Human esophageal cancer stem-like cells escape the cytotoxicity of natural killer cells via down-regulation of ULBP-1","volume":"22","author":"Tang","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_62","first-page":"635","article-title":"The Role of Endothelial Dysfunction in the Mechanism of Gastroesophageal Reflux Disease Development in Patients with Ischemic Heart Disease","volume":"56","author":"Oparin","year":"2017","journal-title":"Acta Clin. Croat."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Sun, J., Ren, H., Wang, J., Xiao, X., Zhu, L., Wang, Y., and Yang, L. (2024). CHAC1: A master regulator of oxidative stress and ferroptosis in human diseases and cancers. Front. Cell Dev. Biol., 12.","DOI":"10.3389\/fcell.2024.1458716"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e12204","DOI":"10.7554\/eLife.12204","article-title":"Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis","volume":"5","author":"Ro","year":"2016","journal-title":"eLife"},{"key":"ref_65","first-page":"3106","article-title":"SLC7A11\/xCT in cancer: Biological functions and therapeutic implications","volume":"10","author":"Lin","year":"2020","journal-title":"Am. J. Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e106183","DOI":"10.15252\/embj.2020106183","article-title":"Dual roles of HSP70 chaperone HSPA1 in quality control of nascent and newly synthesized proteins","volume":"40","author":"Tian","year":"2021","journal-title":"EMBO J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s00418-011-0791-5","article-title":"Differential expression of HSPA1 and HSPA2 proteins in human tissues; tissue microarray-based immunohistochemical study","volume":"135","author":"Scieglinska","year":"2011","journal-title":"Histochem. Cell Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.otohns.2009.08.022","article-title":"Pepsin as a causal agent of inflammation during nonacidic reflux","volume":"141","author":"Samuels","year":"2009","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1159\/000526367","article-title":"Elevated CXCL14 in Induced Sputum Was Associated with Eosinophilic Inflammation and Airway Obstruction in Patients with Asthma","volume":"183","author":"Du","year":"2022","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ejphar.2014.10.034","article-title":"\u2206FosB: A transcriptional regulator of stress and antidepressant responses","volume":"753","author":"Nestler","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1093\/stcltm\/szae064","article-title":"eIF6 modulates skin wound healing by upregulating keratin 6B","volume":"13","author":"Wang","year":"2024","journal-title":"Stem Cells Transl. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/s41575-022-00622-w","article-title":"Mechanisms and pathophysiology of Barrett oesophagus","volume":"19","author":"Souza","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_73","first-page":"3069","article-title":"Identification of key pathways and genes in Barrett\u2019s esophagus using integrated bioinformatics methods","volume":"17","author":"Zhang","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Korbut, E., Janmaat, V.T., Wierdak, M., Hankus, J., W\u00f3jcik, D., Surmiak, M., Magierowska, K., Brzozowski, T., Peppelenbosch, M.P., and Magierowski, M. (2020). Molecular Profile of Barrett\u2019s Esophagus and Gastroesophageal Reflux Disease in the Development of Translational Physiological and Pharmacological Studies. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176436"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Chen, B., Wang, D., Li, J., Hou, Y., and Qiao, C. (2020). Screening and Identification of Prognostic Tumor-Infiltrating Immune Cells and Genes of Endometrioid Endometrial Adenocarcinoma: Based on The Cancer Genome Atlas Database and Bioinformatics. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.554214"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"5382","DOI":"10.1016\/j.asjsur.2023.07.097","article-title":"KRT72 might serves as a prognostic biomarker for patients with prostate cancer","volume":"46","author":"Wang","year":"2023","journal-title":"Asian J. Surg."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.jaci.2013.09.007","article-title":"The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease","volume":"132","author":"Oakley","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Ueki, S., Fujishima, F., Kumagai, T., Ishida, H., Okamoto, H., Takaya, K., Sato, C., Taniyma, Y., Kamei, T., and Sasano, H. (2020). GR, Sgk1, and NDRG1 in esophageal squamous cell carcinoma: Their correlation with therapeutic outcome of neoadjuvant chemotherapy. BMC Cancer, 20.","DOI":"10.1186\/s12885-020-6652-7"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Zhang, T., Li, M., Zhao, S., Zhou, M., Liao, H., Wu, H., Mo, X., Wang, H., Guo, C., and Zhang, H. (2022). CaMK4 Promotes Acute Lung Injury Through NLRP3 Inflammasome Activation in Type II Alveolar Epithelial Cell. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.890710"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"O\u2019Farrell, N.J., Feighery, R., Picardo, S.L., Lynam-Lennon, N., Biniecka, M., McGarrigle, S.A., Phelan, J.J., MacCarthy, F., O\u2019Toole, D., and Fox, E.J. (2016). Changes in mitochondrial stability during the progression of the Barrett\u2019s esophagus disease sequence. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2544-2"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.jcmgh.2016.03.006","article-title":"NOD-Like Receptor Protein 3 Inflammasome Priming and Activation in Barrett\u2019s Epithelial Cells","volume":"2","author":"Nadatani","year":"2016","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.canlet.2014.07.035","article-title":"Differential expression of mitochondrial energy metabolism profiles across the metaplasia-dysplasia-adenocarcinoma disease sequence in Barrett\u2019s oesophagus","volume":"354","author":"Phelan","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1007\/s11596-023-2771-0","article-title":"Roles of MT-ND1 in Cancer","volume":"43","author":"Xu","year":"2023","journal-title":"Curr. Med. Sci."},{"key":"ref_84","first-page":"577","article-title":"Quantitative detection of circulating MT-ND1 as a potential biomarker for colorectal cancer","volume":"21","author":"Xu","year":"2021","journal-title":"Bosn. J. Basic. Med. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Cavalcante, G.C., Ribeiro-Dos-Santos, \u00c2., and de Ara\u00fajo, G.S. (2022). Mitochondria in tumour progression: A network of mtDNA variants in different types of cancer. BMC Genom. Data, 23.","DOI":"10.1186\/s12863-022-01032-2"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"156568","DOI":"10.1016\/j.cyto.2024.156568","article-title":"Pepsin-mediated inflammation in laryngopharyngeal reflux via the ROS\/NLRP3\/IL-1\u03b2 signaling pathway","volume":"178","author":"Tan","year":"2024","journal-title":"Cytokine"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"G411","DOI":"10.1152\/ajpgi.00373.2007","article-title":"Mechanisms of oxidant production in esophageal squamous cell and Barrett\u2019s cell lines","volume":"294","author":"Feagins","year":"2008","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1136\/jcp-2023-208931","article-title":"New kids on the block: FOS and FOSB gene","volume":"76","author":"Cordier","year":"2023","journal-title":"J. Clin. Pathol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/978-3-030-41769-7_17","article-title":"Serum Amyloid A (SAA) Proteins","volume":"94","author":"Sack","year":"2020","journal-title":"Subcell. Biochem."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Huang, G., Li, H., and Zhang, H. (2020). Abnormal Expression of Mitochondrial Ribosomal Proteins and Their Encoding Genes with Cell Apoptosis and Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228879"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.15252\/embj.201694885","article-title":"NSUN3 and ABH1 modify the wobble position of mt-tRNAMet to expand codon recognition in mitochondrial translation","volume":"35","author":"Haag","year":"2016","journal-title":"EMBO J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/s41594-021-00637-y","article-title":"Structural basis of RNA processing by human mitochondrial RNase P","volume":"28","author":"Bhatta","year":"2021","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"32679","DOI":"10.1073\/pnas.2018497117","article-title":"IL-4\/STAT6 signaling facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice","volume":"117","author":"Xu","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Minnone, G., De Benedetti, F., and Bracci-Laudiero, L. (2017). NGF and Its Receptors in the Regulation of Inflammatory Response. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18051028"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"G904","DOI":"10.1152\/ajpgi.00333.2014","article-title":"Human esophageal myofibroblasts secrete proinflammatory cytokines in response to acid and Toll-like receptor 4 ligands","volume":"308","author":"Gargus","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"156251","DOI":"10.1016\/j.phymed.2024.156251","article-title":"Berberine in combination with evodiamine ameliorates gastroesophageal reflux disease through TAS2R38\/TRPV1-mediated regulation of MAPK\/NF-\u03baB signaling pathways and macrophage polarization","volume":"135","author":"Cui","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1080\/21541248.2020.1829914","article-title":"Pathophysiological functions of Rnd proteins","volume":"12","author":"Basbous","year":"2021","journal-title":"Small GTPases"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1111\/j.1600-065X.2012.01099.x","article-title":"NF-\u03baB and the link between inflammation and cancer","volume":"246","author":"DiDonato","year":"2012","journal-title":"Immunol. Rev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1165\/rcmb.2021-0022OC","article-title":"Regulator of Cell Cycle Protein (RGCC\/RGC-32) Protects against Pulmonary Fibrosis","volume":"66","author":"Luzina","year":"2022","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/onc.2010.456","article-title":"Keratins in health and cancer: More than mere epithelial cell markers","volume":"30","author":"Karantza","year":"2011","journal-title":"Oncogene"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Crisponi, L., Buers, I., and Rutsch, F. (2022). CRLF1 and CLCF1 in Development, Health and Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020992"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.tcb.2023.08.004","article-title":"Vimentin at the core of wound healing","volume":"34","author":"Parvanian","year":"2024","journal-title":"Trends Cell Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/imr.12621","article-title":"Overview of the IL-1 family in innate inflammation and acquired immunity","volume":"281","author":"Dinarello","year":"2018","journal-title":"Immunol. Rev."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1080\/00365520410006729","article-title":"Interleukin-8 expression in the esophageal mucosa of patients with gastroesophageal reflux disease","volume":"39","author":"Yoshida","year":"2004","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"475","DOI":"10.5114\/aoms.2017.71933","article-title":"The significance of chemokine CXCL-8 in esophageal carcinoma","volume":"16","author":"Mroczko","year":"2020","journal-title":"Arch. Med. Sci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1002\/lary.23307","article-title":"Pepsin promotes proliferation of laryngeal and pharyngeal epithelial cells","volume":"122","author":"Johnston","year":"2012","journal-title":"Laryngoscope"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12935-019-0772-7","article-title":"Pepsin promotes IL-8 signaling-induced epithelial-mesenchymal transition in laryngeal carcinoma","volume":"19","author":"Tan","year":"2019","journal-title":"Cancer Cell Int."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e230","DOI":"10.1097\/MCG.0b013e3181d47dc4","article-title":"Gastric juice from patients \u201con\u201d acid suppressive therapy can still provoke a significant inflammatory reaction by human bronchial epithelial cells","volume":"44","author":"Mertens","year":"2010","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/BF00609248","article-title":"Effect of high dose omeprazole on gastric pepsin secretion and serum pepsinogen levels in man","volume":"35","author":"Tuynman","year":"1988","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"74","DOI":"10.5056\/jnm19032","article-title":"Salivary Pepsin as an Intrinsic Marker for Diagnosis of Sub-types of Gastroesophageal Reflux Disease and Gastroesophageal Reflux Disease-related Disorders","volume":"26","author":"Wang","year":"2020","journal-title":"J. Neurogastroenterol. Motil."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Olp, M.D., Kalous, K.S., and Smith, B.C. (2020). ICEKAT: An interactive online tool for calculating initial rates from continuous enzyme kinetic traces. BMC Bioinform., 21.","DOI":"10.1186\/s12859-020-3513-y"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"137","DOI":"10.2165\/00003088-200645020-00002","article-title":"Fosamprenavir: Clinical pharmacokinetics and drug interactions of the amprenavir prodrug","volume":"45","author":"Wire","year":"2006","journal-title":"Clin. Pharmacokinet."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"De Felice, F., Malerba, S., Nardone, V., Salvestrini, V., Calomino, N., Testini, M., Boccardi, V., Desideri, I., Gentili, C., and De Luca, R. (2025). Progress and Challenges in Integrating Nutritional Care into Oncology Practice: Results from a National Survey on Behalf of the NutriOnc Research Group. Nutrients, 17.","DOI":"10.3390\/nu17010188"},{"key":"ref_114","unstructured":"Andrews, S. (2024, March 03). Fastqc A Quality Control Tool for High Throughput Sequence Data. Available online: http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1093\/bioinformatics\/bts356","article-title":"RSeQC: Quality control of RNA-seq experiments","volume":"28","author":"Wang","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Kalari, K.R., Nair, A.A., Bhavsar, J.D., O\u2019Brien, D.R., Davila, J.I., Bockol, M.A., Nie, J., Tang, X., Baheti, S., and Doughty, J.B. (2014). MAP-RSeq: Mayo Analysis Pipeline for RNA sequencing. BMC Bioinform., 15.","DOI":"10.1186\/1471-2105-15-224"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Green","year":"2014","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6182\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:59:41Z","timestamp":1760032781000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6182"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,26]]},"references-count":119,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26136182"],"URL":"https:\/\/doi.org\/10.3390\/ijms26136182","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,26]]}}}