{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T01:54:47Z","timestamp":1788400487127,"version":"build-2803163510"},"reference-count":82,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T00:00:00Z","timestamp":1738108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Aboca SpA Societ\u00e0 Agricola, Localit\u00e0 Aboca 20"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>When the protective mechanisms of the gastroesophageal mucosa are overwhelmed by injurious factors, the structural and functional mucosal integrity is compromised, resulting in a wide spectrum of disorders. Poliprotect has recently been shown to be non-inferior to standard-dose omeprazole for the treatment of endoscopy-negative patients with heartburn and\/or epigastric pain or burning. Here, we provide preclinical data describing the mechanism of action of the Poliprotect formulation, a 100% natural, biodegradable, and environmental friendly medical device according to EU 2017\/745 and containing UVCB (unknown or variable composition, complex-reaction products, or biological materials) substances of botanical and mineral origin, according to the REACH and European Chemical Agency definitions. Different in vitro assays demonstrated the capability of Poliprotect to adhere to mucus-secreting gastric cells and concomitantly deliver a local barrier with buffering and antioxidant activity. In studies conducted in accordance with systems biology principles, we evaluated the effects of this barrier on human gastric cells exposed to acidic stress. Biological functions identified via Ingenuity Pathway Analysis highlighted the product\u2019s ability to create a microenvironment that supports the mucosal structural and functional integrity, promotes healing, and restores a balanced mucosal inflammatory status. Additionally, transepithelial electrical resistance and an Ussing chamber showed the product\u2019s capability of preserving the integrity of the gastric and esophageal epithelial barriers when exposed to an acid solution. Two in vivo models of erosive gastropathy further highlighted its topical protection against ethanol- and drug-induced mucosal injury. Overall, our findings sustain the feasibility of a paradigm shift in therapeutics R&amp;D by depicting a very innovative and desirable mode of interaction with the human body based on the emerging biophysical, rather than the pharmacological properties of these therapeutic agents.<\/jats:p>","DOI":"10.3390\/ijms26031181","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T04:01:39Z","timestamp":1738209699000},"page":"1181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Non-Pharmacological Paradigm Captures the Complexity in the Mechanism of Action of Poliprotect Against Gastroesophageal Reflux Disease and Dyspepsia"],"prefix":"10.3390","volume":"26","author":[{"given":"Sara","family":"Caterbi","sequence":"first","affiliation":[{"name":"Bios-Therapy, Physiological Systems for Health S.p.A., Localit\u00e0 Aboca 20, 52037 Sansepolcro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Buttarini","sequence":"additional","affiliation":[{"name":"Bios-Therapy, Physiological Systems for Health S.p.A., Localit\u00e0 Aboca 20, 52037 Sansepolcro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Garetto","sequence":"additional","affiliation":[{"name":"Bios-Therapy, Physiological Systems for Health S.p.A., Localit\u00e0 Aboca 20, 52037 Sansepolcro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Franco Moscardini","sequence":"additional","affiliation":[{"name":"Bios-Therapy, Physiological Systems for Health S.p.A., Localit\u00e0 Aboca 20, 52037 Sansepolcro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Ughetto","sequence":"additional","affiliation":[{"name":"Bios-Therapy, Physiological Systems for Health S.p.A., Localit\u00e0 Aboca 20, 52037 Sansepolcro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Bios-Therapy, Physiological Systems for Health S.p.A., Localit\u00e0 Aboca 20, 52037 Sansepolcro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Panizzi","sequence":"additional","affiliation":[{"name":"Bios-Therapy, Physiological Systems for Health S.p.A., Localit\u00e0 Aboca 20, 52037 Sansepolcro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2593-7620","authenticated-orcid":false,"given":"Cristiano","family":"Rumio","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Biomolecular Sciences, University of Milan, Via Trentacoste 2, 20134 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Mattioli","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Public Health, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Perfumi","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Public Health, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Maidecchi","sequence":"additional","affiliation":[{"name":"Aboca S.p.A, Societ\u00e0 Agricola, Localit\u00e0 Aboca 20, 52037 Sansepolcro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cossu","sequence":"additional","affiliation":[{"name":"Aboca S.p.A, Societ\u00e0 Agricola, Localit\u00e0 Aboca 20, 52037 Sansepolcro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislas","family":"Bruley des Varannes","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Hepatology and Clinical Oncology, Institut des Maladies de l\u2019Appareil Digestif, Universitary Hospital, 44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7071-3151","authenticated-orcid":false,"given":"Jaroslaw","family":"Regula","sequence":"additional","affiliation":[{"name":"Department of Oncological Gastroenterology, Maria Sklodowska-Curie National Research Institute of Oncology, 00-001 Warsaw, Poland"},{"name":"Department of Gastroenterology, Hepatology and Clinical Oncology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Malfertheiner","sequence":"additional","affiliation":[{"name":"LMU Klinikum Medizinische Klinik und Poliklinik II, Campus Gro\u00dfhadern, Marchioninistr. 15, 81377 M\u00fcnchen, Germany"},{"name":"Otto-von-Guericke Universit\u00e4t Magdeburg Klinik f\u00fcr Gastroenterologie, Hepatologie und Infektiologie, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Sardi","sequence":"additional","affiliation":[{"name":"Bios-Therapy, Physiological Systems for Health S.p.A., Localit\u00e0 Aboca 20, 52037 Sansepolcro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacopo","family":"Lucci","sequence":"additional","affiliation":[{"name":"Bios-Therapy, Physiological Systems for Health S.p.A., Localit\u00e0 Aboca 20, 52037 Sansepolcro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.cgh.2017.06.035","article-title":"The Esophageal Epithelial Barrier in Health and Disease","volume":"16","author":"Blevins","year":"2018","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1053\/j.gastro.2008.05.030","article-title":"Gastric Mucosal Defense and Cytoprotection: Bench to Bedside","volume":"135","author":"Laine","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1159\/000357855","article-title":"Gastric Barrier Function and Toxic Damage","volume":"32","author":"Niv","year":"2014","journal-title":"Dig. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.bpg.2010.08.008","article-title":"The integrity of the esophageal mucosa. Balance between offensive and defensive mechanisms","volume":"24","author":"Orlando","year":"2010","journal-title":"Best Pr. Res. Clin. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7210","DOI":"10.2741\/3223","article-title":"Oxidative stress-induced disruption of epithelial and endothelial tight junctions","volume":"13","author":"Rao","year":"2008","journal-title":"Front. Biosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1152\/physrev.00004.2008","article-title":"Prostaglandins, NSAIDs, and Gastric Mucosal Protection: Why Doesn\u2019t the Stomach Digest Itself?","volume":"88","author":"Wallace","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-62795-1","article-title":"Global Prevalence and Risk Factors of Gastro-oesophageal Reflux Disease (GORD): Systematic Review with Meta-analysis","volume":"10","author":"Nirwan","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_8","first-page":"1","article-title":"Global prevalence of functional dyspepsia according to Rome criteria, 1990\u20132020: A systematic review and meta-analysis","volume":"14","author":"Lee","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_9","first-page":"1739","article-title":"What is the Prevalence of Clinically Significant Endoscopic Findings in Subjects With Dyspepsia? Updated Systematic Review and Meta-analysis","volume":"21","author":"Mousavian","year":"2022","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Black, C.J., Houghton, L.A., and Ford, C.A. (2018). Insights into the evaluation and management of dyspepsia: Recent developments and new guidelines. Ther. Adv. Gastroenterol., 11.","DOI":"10.1177\/1756284818805597"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1080\/17512433.2020.1752664","article-title":"Pathophysiology, diagnosis, and pharmacological treatment of gastro-esophageal reflux disease","volume":"13","author":"Savarino","year":"2020","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1053\/j.gastro.2016.02.012","article-title":"Esophageal Disorders","volume":"150","author":"Aziz","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/nyas.13169","article-title":"Between GERD and NERD: The relevance of weakly acidic reflux","volume":"1380","author":"Ottonello","year":"2016","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1056\/NEJMra1501505","article-title":"Functional Dyspepsia","volume":"373","author":"Talley","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1053\/j.gastro.2017.07.017","article-title":"Superficial Esophageal Mucosal Afferent Nerves May Contribute to Reflux Hypersensitivity in Nonerosive Reflux Disease","volume":"153","author":"Woodland","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1136\/gut.2007.133470","article-title":"Determinants of gastro-oesophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors","volume":"57","author":"Zerbib","year":"2007","journal-title":"Gut"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ajg.2016.499","article-title":"Pathophysiological Abnormalities in Functional Dyspepsia Subgroups According to the Rome III Criteria","volume":"112","author":"Vanheel","year":"2017","journal-title":"Am. J. Gastroenterol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"27","DOI":"10.14309\/ajg.0000000000001538","article-title":"ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease","volume":"117","author":"Katz","year":"2021","journal-title":"Am. J. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/ajg.2017.154","article-title":"ACG and CAG Clinical Guideline: Management of Dyspepsia","volume":"112","author":"Moayyedi","year":"2017","journal-title":"Am. J. Gastroenterol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Patel, K., and Dunn, J. (2015). Updated NICE Guidance on the Management of Dyspepsia, John Wiley & Sons, Inc.","DOI":"10.1002\/psb.1306"},{"key":"ref_21","first-page":"CD011194","article-title":"Proton pump inhibitors for functional dyspepsia","volume":"2018","author":"Yuan","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_22","first-page":"CD002095","article-title":"Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease","volume":"2013","author":"Sigterman","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_23","first-page":"CD003244","article-title":"Medical treatments in the short term management of reflux oesophagitis","volume":"2007","author":"Khan","year":"2007","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1017\/ice.2019.23","article-title":"Risk factors for Clostridium difficile infection in pediatric inpatients: A meta-analysis and systematic review","volume":"40","author":"Anjewierden","year":"2019","journal-title":"Infect. Control. Hosp. Epidemiol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Dipasquale, V., Cicala, G., Spina, E., and Romano, C. (2022). A Narrative Review on Efficacy and Safety of Proton Pump Inhibitors in Children. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.839972"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1177\/1060028018760569","article-title":"The Risk of Community-Acquired Enteric Infection in Proton Pump Inhibitor Therapy: Systematic Review and Meta-analysis","volume":"52","author":"Hafiz","year":"2018","journal-title":"Ann. Pharmacother."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Huang, C.-H., Tsai, C.-J., Su, C.-C., Yen, C.-T., Chen, J.-L., and Cheng, C.-L. (2024). Accelerated risk of renal disease progression in pre-ESRD patients with proton pump inhibitors use: A nationwide population-based study. BMC Nephrol., 25.","DOI":"10.1186\/s12882-024-03867-6"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1177\/10600280211039240","article-title":"Proton Pump Inhibitors and the Risk of Community-Acquired Pneumonia: An Updated Meta-analysis","volume":"56","author":"Xun","year":"2021","journal-title":"Ann. Pharmacother."},{"key":"ref_29","first-page":"CD001960","article-title":"Pharmacological interventions for non-ulcer dyspepsia","volume":"4","author":"Moayyedi","year":"2006","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1111\/apt.12007","article-title":"Partial symptom-response to proton pump inhibitors in patients with non-erosive reflux disease or reflux oesophagitis\u2014A post hoc analysis of 5796 patients","volume":"36","author":"Bytzer","year":"2012","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1365-2036.2012.05128.x","article-title":"Review article: Current treatment options and management of functional dyspepsia","volume":"36","author":"Lacy","year":"2012","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_32","first-page":"1","article-title":"A review of medical therapy for proton pump inhibitor nonresponsive gastroesophageal reflux disease","volume":"30","author":"Hillman","year":"2017","journal-title":"Dis. Esophagus"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e14238","DOI":"10.1111\/nmo.14238","article-title":"United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia","volume":"33","author":"Wauters","year":"2021","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1080\/14656566.2024.2416585","article-title":"Pharmacological management of gastro-esophageal reflux disease: State of the art in 2024","volume":"25","author":"Visaggi","year":"2024","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e14774","DOI":"10.1111\/nmo.14774","article-title":"Prokinetics-safety and efficacy: The European Society of Neurogastroenterology and Motility\/The American Neurogastroenterology and Motility Society expert review","volume":"36","author":"Bor","year":"2024","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/jgh.15208","article-title":"Effects of the herbal medicine Rikkunshito, for functional dyspepsia: A systematic review and meta-analysis","volume":"36","author":"Ko","year":"2020","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Savarino, V., Marabotto, E., Zentilin, P., Furnari, M., Bodini, G., Giannini, E.G., and Savarino, V.E. (2023). Gastrointestinal functional disorders can benefit from the use of medical devices made of substances. Front. Drug Saf. Regul., 3.","DOI":"10.3389\/fdsfr.2023.1119353"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1111\/apt.13914","article-title":"Randomised clinical trial: Mucosal protection combined with acid suppression in the treatment of non-erosive reflux disease\u2014Efficacy of Esoxx, a hyaluronic acid\u2013chondroitin sulphate based bioadhesive formulation","volume":"45","author":"Savarino","year":"2017","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.14309\/ajg.0000000000002360","article-title":"Poliprotect vs Omeprazole in the Relief of Heartburn, Epigastric Pain, and Burning in Patients Without Erosive Esophagitis and Gastroduodenal Lesions: A Randomized, Controlled Trial","volume":"118","author":"Corazziari","year":"2023","journal-title":"Am. J. Gastroenterol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1111\/j.1442-2050.2011.01276.x","article-title":"Efficacy of adding sodium alginate to omeprazole in patients with nonerosive reflux disease: A randomized clinical trial","volume":"25","author":"Manabe","year":"2011","journal-title":"Dis. Esophagus"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1111\/apt.13567","article-title":"Randomised clinical trial: Alginate (Gaviscon Advance) vs. placebo as add-on therapy in reflux patients with inadequate response to a once daily proton pump inhibitor","volume":"43","author":"Reimer","year":"2016","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"244","DOI":"10.5114\/pg.2017.72097","article-title":"The role of pH in symptomatic relief and effective treatment of gastroesophageal reflux disease","volume":"4","year":"2017","journal-title":"Gastroenterol. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6706","DOI":"10.3748\/wjg.v26.i43.6706","article-title":"Gastric acid level of humans must decrease in the future","volume":"26","author":"Fujimori","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_44","first-page":"107","article-title":"TEER Measurement Techniques for In Vitro Barrier Model Systems","volume":"20","author":"Srinivasan","year":"2015","journal-title":"JALA: J. Assoc. Lab. Autom."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.bbrc.2011.07.106","article-title":"The NCI-N87 cell line as a gastric epithelial barrier model for drug permeability assay","volume":"412","author":"Lemieux","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/nyas.14501","article-title":"Pathophysiology and treatment options for gastroesophageal reflux disease: Looking beyond acid","volume":"1486","author":"Sharma","year":"2020","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_47","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_48","doi-asserted-by":"crossref","unstructured":"Greco, C.M., Garetto, S., Montellier, E., Liu, Y., Chen, S., Baldi, P., Sassone-Corsi, P., and Lucci, J. (2020). A non-pharmacological therapeutic approach in the gut triggers distal metabolic rewiring capable of ameliorating diet-induced dysfunctions encompassed by metabolic syndrome. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-69469-y"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Parisio, C., Lucarini, E., Micheli, L., Toti, A., Mannelli, L.D.C., Antonini, G., Panizzi, E., Maidecchi, A., Giovagnoni, E., and Lucci, J. (2019). Researching New Therapeutic Approaches for Abdominal Visceral Pain Treatment: Preclinical Effects of an Assembled System of Molecules of Vegetal Origin. Nutrients, 12.","DOI":"10.3390\/nu12010022"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4","DOI":"10.36118\/pharmadvances.01.2020.02s","article-title":"The concept of non-pharmacological mechanism of action in medical devices made of substances in practice: What pharmacology can do to promote the scientific implementation of the European medical device regulation","volume":"1","author":"Racchi","year":"2020","journal-title":"Pharmadvances"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e14022","DOI":"10.1111\/nmo.14022","article-title":"Mucosal pathogenesis in gastro-esophageal reflux disease","volume":"32","author":"Ustaoglu","year":"2020","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1053\/j.gastro.2004.08.014","article-title":"The pathogenesis of heartburn in nonerosive reflux disease: A unifying hypothesis","volume":"128","author":"Barlow","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1136\/gut.2007.141804","article-title":"Short exposure of oesophageal mucosa to bile acids, both in acidic and weakly acidic conditions, can impair mucosal integrity and provoke dilated intercellular spaces","volume":"57","author":"Farre","year":"2008","journal-title":"Gut"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/apt.16072","article-title":"Systematic review and network meta-analysis: Efficacy of drugs for functional dyspepsia","volume":"53","author":"Ford","year":"2020","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e13719","DOI":"10.1111\/nmo.13719","article-title":"Impaired gastric mucosal integrity identified by confocal endomicroscopy in Helicobacter pylori-negative functional dyspepsia","volume":"32","author":"Ji","year":"2019","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Khalil, M., Perniola, V., Lanza, E., Mahdi, L., Sallustio, P., Idone, V., Semeraro, D., Mastrodonato, M., Testini, M., and Desaphy, J.-F. (2025). Poliprotect\u00ae, a Medical Device Made of Substances, Potently Protects the Human Esophageal Mucosa Challenged by Multiple Agents: Evidence from In Vitro and Ex Vivo Electrophysiological Models. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26020791"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e1187325","DOI":"10.1080\/21688370.2016.1187325","article-title":"Indomethacin induces increase in gastric epithelial tight junction permeability via redistribution of occludin and activation of p38 MAPK in MKN-28 Cells","volume":"4","author":"Blikslager","year":"2016","journal-title":"Tissue Barriers"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1248\/bpb.26.651","article-title":"Protective Effects of Polygodial on Gastric Mucosal Lesions Induced by Necrotizing Agents in Rats and the Possible Mechanisms of Action","volume":"26","author":"Pongpiriyadacha","year":"2003","journal-title":"Biol. Pharm. Bull."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.3748\/wjg.v18.i18.2147","article-title":"Pathogenesis of NSAID-induced gastric damage: Importance of cyclooxygenase inhibition and gastric hypermotility","volume":"18","author":"Takeuchi","year":"2012","journal-title":"World J. Gastroenterol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"969831","DOI":"10.3389\/fdsfr.2022.969831","article-title":"Effectiveness and tolerability of Poliprotect, a natural mucosal protective agent for gastroesophageal reflux disease and dyspepsia: Surveys from patients, physicians, and pharmacists","volume":"2","author":"Cioeta","year":"2022","journal-title":"Front. Drug Saf. Regul."},{"key":"ref_61","first-page":"1","article-title":"Suspect screening analysis to improve untargeted and targeted UHPLC-qToF approaches: The biodegradability of a proton pump inhibitor medicine and a natural medical device","volume":"14","author":"Mattoli","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_62","unstructured":"(2003). Aboca. Composition for Use in the Treatment of GI in Patients for Which Treatment with PPI Is. (WO2003066022A2), Unadvisable. Patent."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.foodhyd.2017.05.043","article-title":"Mucoadhesion: A food perspective","volume":"72","author":"Cook","year":"2017","journal-title":"Food Hydrocoll."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Mackie, A.R., Goycoolea, F.M., Menchicchi, B., Caramella, C.M., Saporito, F., Lee, S., Stephansen, K., Chronakis, I.S., Hiorth, M., and Adamczak, M. (2017). Innovative Methods and Applications in Mucoadhesion Research. Macromol. Biosci., 17.","DOI":"10.1002\/mabi.201600534"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Pota\u015b, J., Szyma\u0144ska, E., Basa, A., Hafner, A., and Winnicka, K. (2020). Tragacanth Gum\/Chitosan Polyelectrolyte Complexes-Based Hydrogels Enriched with Xanthan Gum as Promising Materials for Buccal Application. Materials, 14.","DOI":"10.3390\/ma14010086"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1211\/0022357044085","article-title":"Mucoadhesive and penetration enhancement properties of three grades of hyaluronic acid using porcine buccal and vaginal tissue, Caco-2 cell lines, and rat jejunum","volume":"56","author":"Sandri","year":"2004","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1039\/C3FO60702J","article-title":"A standardised static in vitro digestion method suitable for food\u2014An international consensus","volume":"5","author":"Minekus","year":"2014","journal-title":"Food Funct."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Page, M.J., Kell, D.B., and Pretorius, E. (2022). The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. Chronic Stress, 6.","DOI":"10.1177\/24705470221076390"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1016\/j.bbamcr.2014.05.014","article-title":"Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease","volume":"1843","author":"Turner","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.foodchem.2014.11.128","article-title":"A Caco-2 cell-based quantitative antioxidant activity assay for antioxidants","volume":"175","author":"Wan","year":"2015","journal-title":"Food Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"8896","DOI":"10.1021\/jf0715166","article-title":"Cellular Antioxidant Activity (CAA) Assay for Assessing Antioxidants, Foods, and Dietary Supplements","volume":"55","author":"Wolfe","year":"2007","journal-title":"J. Agric. Food Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/2000-1967-106","article-title":"Acid Transport through Gastric Mucus","volume":"109","author":"Phillipson","year":"2004","journal-title":"Upsala J. Med Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.dld.2004.03.008","article-title":"Duodenal alkaline secretion: Its mechanisms and role in mucosal protection against gastric acid","volume":"36","author":"Konturek","year":"2004","journal-title":"Dig. Liver Dis."},{"key":"ref_74","first-page":"G599","article-title":"A physics-based model for maintenance of the pH gradient in the gastric mucus layer","volume":"313","author":"Lewis","year":"2017","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_75","first-page":"303","article-title":"Saliva between normal and pathological. Important factors in determining systemic and oral health","volume":"2","author":"Iorgulescu","year":"2010","journal-title":"J. Med. Life"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/1475-2891-10-114","article-title":"The role of a pre-load beverage on gastric volume and food intake: Comparison between non-caloric carbonated and non-carbonated beverage","volume":"10","author":"Cuomo","year":"2011","journal-title":"Nutr. J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"G1151","DOI":"10.1152\/ajpgi.90649.2008","article-title":"A guide to Ussing chamber studies of mouse intestine","volume":"296","author":"Clarke","year":"2009","journal-title":"Am. J. Physiol.\u2014Gastrointest. Liver Physiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.jcf.2004.05.026","article-title":"Transepithelial electrical measurements with the Ussing chamber","volume":"3","author":"Li","year":"2004","journal-title":"J. Cyst. Fibros."},{"key":"ref_80","first-page":"977","article-title":"Fluvoxamine inhibits some inflammatory genes expression in LPS\/stimulated human endothelial cells, U937 macrophages, and carrageenan-induced paw edema in rat","volume":"19","author":"Rafiee","year":"2016","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2779","DOI":"10.1073\/pnas.76.6.2779","article-title":"Human promyelocytic leukemia cells in culture differentiate into macrophage-like cells when treated with a phorbol diester","volume":"76","author":"Rovera","year":"1979","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0028-3908(97)00195-0","article-title":"Tachykinin NK1 and NK2 receptor-mediated control of peristaltic propulsion in the guinea-pig small intestine in vitro","volume":"37","author":"Holzer","year":"1998","journal-title":"Neuropharmacology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/3\/1181\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:38:34Z","timestamp":1759919914000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/3\/1181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,29]]},"references-count":82,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ijms26031181"],"URL":"https:\/\/doi.org\/10.3390\/ijms26031181","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,29]]}}}