{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:09:54Z","timestamp":1781842194483,"version":"3.54.5"},"reference-count":21,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T00:00:00Z","timestamp":1731542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Clinical Trial Center of Korea University Anam Hospital","award":["I1502411"],"award-info":[{"award-number":["I1502411"]}]},{"name":"Clinical Trial Center of Korea University Anam Hospital","award":["NRF2018R1D1A1A09083263"],"award-info":[{"award-number":["NRF2018R1D1A1A09083263"]}]},{"name":"Clinical Trial Center of Korea University Anam Hospital","award":["2021R1F1A1056645 (RS-2021-NR063002)"],"award-info":[{"award-number":["2021R1F1A1056645 (RS-2021-NR063002)"]}]},{"name":"Clinical Trial Center of Korea University Anam Hospital","award":["2023R1A2C1004538 (RS-2023-NR076554)"],"award-info":[{"award-number":["2023R1A2C1004538 (RS-2023-NR076554)"]}]},{"name":"Ministry of Education","award":["I1502411"],"award-info":[{"award-number":["I1502411"]}]},{"name":"Ministry of Education","award":["NRF2018R1D1A1A09083263"],"award-info":[{"award-number":["NRF2018R1D1A1A09083263"]}]},{"name":"Ministry of Education","award":["2021R1F1A1056645 (RS-2021-NR063002)"],"award-info":[{"award-number":["2021R1F1A1056645 (RS-2021-NR063002)"]}]},{"name":"Ministry of Education","award":["2023R1A2C1004538 (RS-2023-NR076554)"],"award-info":[{"award-number":["2023R1A2C1004538 (RS-2023-NR076554)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Laryngopharyngeal reflux disease (LPRD) is a prevalent upper airway disorder characterized by inflammation and epithelial damage due to the backflow of gastric contents. Current treatments, primarily proton pump inhibitors (PPIs), often show variable efficacy, necessitating the exploration of alternative or adjunctive therapies. This study investigates the therapeutic potential of a mixture of Hedera helix and Coptidis rhizome (HHCR) in mitigating the pathophysiological mechanisms of LPRD. Using an in vitro model of human pharyngeal epithelial cells exposed to acidic conditions, we observed that acid exposure significantly increased the expression of adenosine A3 receptor (adenosine A3) and matrix metalloproteinase-7 (MMP-7), leading to E-cadherin cleavage and compromised epithelial integrity. Treatment with the HHCR mixture effectively suppressed adenosine A3 expression and MMP-7 activity, thereby reducing E-cadherin cleavage and preserving cellular cohesion. These results highlight the HHCR mixture\u2019s ability to modulate the adenosine A3\u2013MMP-7\u2013E-cadherin pathway, suggesting its potential as a valuable adjunctive therapy for LPRD, particularly for patients unresponsive to conventional PPI treatment. This study provides new insights into the molecular interactions involved in LPRD and supports further clinical evaluation of HHCR as a complementary treatment option.<\/jats:p>","DOI":"10.3390\/ijms252212244","type":"journal-article","created":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T08:06:32Z","timestamp":1731571592000},"page":"12244","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Inhibitory Effect of Hedera helix and Coptidis Rhizome Mixture in the Pathogenesis of Laryngopharyngeal Reflux: Cleavage of E-Cadherin in Acid-Exposed Primary Human Pharyngeal Epithelial Cells"],"prefix":"10.3390","volume":"25","author":[{"given":"Nu-Ri","family":"Im","sequence":"first","affiliation":[{"name":"Department of Efficacy Evaluation and Diagnosis Team, Zymedi, Incheon 21983, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7186-4290","authenticated-orcid":false,"given":"Byoungjae","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul 02841, Republic of Korea"},{"name":"Neuroscience Research Institute, College of Medicine, Korea University, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You Yeon","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwang-Yoon","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Kuk","family":"Baek","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1177\/0194599819827488","article-title":"Evaluation and Management of Laryngopharyngeal Reflux Disease: State of the Art Review","volume":"160","author":"Lechien","year":"2019","journal-title":"Otolaryngol. Head. Neck Surg."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lechien, J.R., Saussez, S., Muls, V., Barillari, M.R., Chiesa-Estomba, C.M., Hans, S., and Karkos, P.D. (2020). Laryngopharyngeal Reflux: A State-of-the-Art Algorithm Management for Primary Care Physicians. J. Clin. Med., 9.","DOI":"10.20944\/preprints202010.0364.v1"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1097\/00005537-200208000-00014","article-title":"Perspectives in laryngopharyngeal reflux: An international survey","volume":"112","author":"Book","year":"2002","journal-title":"Laryngoscope"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.otohns.2008.06.003","article-title":"Double-blind, placebo-controlled trial with esomeprazole for symptoms and signs associated with laryngopharyngeal reflux","volume":"139","author":"Reichel","year":"2008","journal-title":"Otolaryngol. Head. Neck Surg."},{"key":"ref_5","first-page":"184","article-title":"Laryngopharyngeal reflux: Diagnosis, treatment, and latest research","volume":"18","author":"Campagnolo","year":"2014","journal-title":"Int. Arch. Otorhinolaryngol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1002\/lary.27591","article-title":"Clinical outcomes of laryngopharyngeal reflux treatment: A systematic review and meta-analysis","volume":"129","author":"Lechien","year":"2019","journal-title":"Laryngoscope"},{"key":"ref_7","first-page":"CD004823","article-title":"Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults","volume":"2011","author":"Chang","year":"2011","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.molmed.2007.07.001","article-title":"From traditional Chinese medicine to rational cancer therapy","volume":"13","author":"Efferth","year":"2007","journal-title":"Trends Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"819","DOI":"10.3349\/ymj.2015.56.3.819","article-title":"Expectorant and antitussive effect of Hedera helix and Rhizoma coptidis extracts mixture","volume":"56","author":"Song","year":"2015","journal-title":"Yonsei Med. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.phymed.2006.05.003","article-title":"Tolerance, safety and efficacy of Hedera helix extract in inflammatory bronchial diseases under clinical practice conditions: A prospective, open, multicentre postmarketing study in 9657 patients","volume":"16","author":"Fazio","year":"2009","journal-title":"Phytomedicine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1089\/jmf.2019.4568","article-title":"Protective Effect of GHX02 Extract on Particulate Matter-Induced Lung Injury","volume":"23","author":"Yang","year":"2020","journal-title":"J. Med. Food"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.21037\/jtd.2020.03.61","article-title":"The clinical efficacy of AG NPP709 (Synatura((R))) in patients with chronic bronchitis type stable chronic obstructive pulmonary disease","volume":"12","author":"Lee","year":"2020","journal-title":"J. Thorac. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Im, N.R., Lee, D.Y., Kim, B., Kim, J., Jung, K.Y., Kim, T.H., and Baek, S.K. (2019). Role of Matrix Metalloproteinases 7 in the Pathogenesis of Laryngopharyngeal Reflux: Decreased E-cadherin in Acid exposed Primary Human Pharyngeal Epithelial Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215276"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"18","DOI":"10.2174\/1573403X12666160111125116","article-title":"Adenosine A3 Receptor: A promising therapeutic target in cardiovascular disease","volume":"12","author":"Nishat","year":"2016","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"61690","DOI":"10.18632\/oncotarget.11435","article-title":"CD73 is associated with poor prognosis in HNSCC","volume":"7","author":"Ren","year":"2016","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/lary.1991.101.s53.1","article-title":"The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): A clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury","volume":"101","author":"Koufman","year":"1991","journal-title":"Laryngoscope"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.12998\/wjcc.v7.i19.2995","article-title":"Treatment of laryngopharyngeal reflux disease: A systematic review","volume":"7","author":"Lechien","year":"2019","journal-title":"World J. Clin. Cases"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1111\/coa.13395","article-title":"The management of suspected or confirmed laryngopharyngeal reflux patients with recalcitrant symptoms: A contemporary review","volume":"44","author":"Lechien","year":"2019","journal-title":"Clin. Otolaryngol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1124\/pr.111.005116","article-title":"Antitussive drugs\u2014Past, present, and future","volume":"66","author":"Dicpinigaitis","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s00109-021-02166-z","article-title":"Matrix metalloproteinase-7 induces E-cadherin cleavage in acid-exposed primary human pharyngeal epithelial cells via the ROS\/ERK\/c-Jun pathway","volume":"100","author":"Im","year":"2022","journal-title":"J. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1002\/lary.20764","article-title":"Rhinovirus infection-induced alteration of tight junction and adherens junction components in human nasal epithelial cells","volume":"120","author":"Yeo","year":"2010","journal-title":"Laryngoscope"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/22\/12244\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:32:26Z","timestamp":1760113946000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/22\/12244"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,14]]},"references-count":21,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["ijms252212244"],"URL":"https:\/\/doi.org\/10.3390\/ijms252212244","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,14]]}}}