{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:22:15Z","timestamp":1790504535440,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T00:00:00Z","timestamp":1614297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"China Medical University and Hospital, Taichung, Taiwan","award":["CMU103-BC-2, DMR-104-026, DMR-107-040 and DMR-108-038"],"award-info":[{"award-number":["CMU103-BC-2, DMR-104-026, DMR-107-040 and DMR-108-038"]}]},{"name":"Taiwan Ministry of Science and Technology","award":["MOST109-2811-B-005-518 and MOST109-2314-B-039-016"],"award-info":[{"award-number":["MOST109-2811-B-005-518 and MOST109-2314-B-039-016"]}]},{"name":"Ministry of Education of Taiwan","award":["MOE-109-S-0023-A"],"award-info":[{"award-number":["MOE-109-S-0023-A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Hypopharyngeal squamous cell carcinoma (HSCC) is usually diagnosed at an advanced stage, leading to a poor prognosis. Even after improvement of surgical techniques, chemotherapy, and radiation technology, the survival rate of HSCC remains poor. Metformin, which is commonly used for type 2 diabetes mellitus (DM), has been suggested to reduce the risk of various cancer types. However, only a few clinical studies mentioned the relationship between metformin use and HSCC. Hence, the aim of this study was to elucidate the specific effect and mechanism of action of metformin in hypopharyngeal cancer. We first assessed whether metformin use has an effect on hypopharyngeal cancer patients with DM by conducting a retrospective cohort study. Our results showed that DM hypopharyngeal cancer patients who used metformin exhibited significantly better overall survival rates than that without metformin treatment. The cell-based analysis further indicated that metformin treatment regulated p38\/JNK pathway to reduce Cyclin D1 and Bcl-2 expressions. In addition, metformin activated the pathways of AMPK\u03b1 and MEK\/ERK to phosphorylate p27(Thr198) and reduce mTOR phosphorylation in cells. These actions direct cells toward G1 cell cycle arrest, apoptosis, and autophagy. Our results, through combining a clinical cohort analysis with an in vitro study, demonstrate that metformin can be used for drug repositioning in the treatment of DM patients with hypopharyngeal cancer.<\/jats:p>","DOI":"10.3390\/ph14030191","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T09:47:20Z","timestamp":1614332840000},"page":"191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Metformin Increases Survival in Hypopharyngeal Cancer Patients with Diabetes Mellitus: Retrospective Cohort Study and Cell-Based Analysis"],"prefix":"10.3390","volume":"14","author":[{"given":"Yung-An","family":"Tsou","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung 406, Taiwan"},{"name":"Department of Life Sciences, Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Chao","family":"Chang","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Graduate Institute of Biomedical Sciences, China Medical University, Taichung 406, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Der","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung 406, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ro-Lin","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Hsui","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung 406, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang-Chun","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung 406, Taiwan"},{"name":"Center for Molecular Medicine, Graduate Institute of Biomedical Sciences, China Medical University, Taichung 406, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3137-3833","authenticated-orcid":false,"given":"Theresa","family":"Staniczek","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Center of Excellence in Dermatology, Heidelberg University, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsu-Fang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung 406, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Ying","family":"Hsu","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Graduate Institute of Biomedical Sciences, China Medical University, Taichung 406, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5546-5874","authenticated-orcid":false,"given":"Wen-Dien","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Sport Performance, National Taiwan University of Sport, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7145-784X","authenticated-orcid":false,"given":"Chih-Ho","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan"},{"name":"Department of Pediatrics, Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Linkou 333, Taiwan"},{"name":"Department of Microbiology, School of Medicine, China Medical University, Taichung 406, Taiwan"},{"name":"Department of Nursing, Asia University, Taichung 413, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2461-9150","authenticated-orcid":false,"given":"Chuan-Mu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan"},{"name":"The iEGG and Animal Biotechnology Center, Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, 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Surg. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.oraloncology.2019.01.014","article-title":"Organ preservation in laryngeal and hypopharyngeal cancer","volume":"90","author":"Kang","year":"2019","journal-title":"Oral Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s00784-018-2444-8","article-title":"Survivin expression in head and neck squamous cell carcinomas is frequent and correlates with clinical parameters and treatment outcomes","volume":"23","author":"Munscher","year":"2019","journal-title":"Clin. Oral Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"104851","DOI":"10.1016\/j.oraloncology.2020.104851","article-title":"Expression of let-7i and miR-192 is associated with resistance to cisplatin-based chemoradiotherapy in patients with larynx and hypopharynx cancer","volume":"109","author":"Poel","year":"2020","journal-title":"Oral Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/s41419-019-1769-9","article-title":"Clinical update on head and neck cancer: Molecular biology and ongoing challenges","volume":"10","author":"Alsahafi","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Vossen, D.M., Verhagen, C.V.M., van der Heijden, M., Essers, P.B.M., Bartelink, H., Verheij, M., Wessels, L.F.A., van den Brekel, M.W.M., and Vens, C. (2019). Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy. Cancers, 11.","DOI":"10.3390\/cancers11040445"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1007\/s00125-017-4318-z","article-title":"Metformin: Historical overview","volume":"60","author":"Bailey","year":"2017","journal-title":"Diabetologia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1007\/s00125-017-4336-x","article-title":"Metformin: Clinical use in type 2 diabetes","volume":"60","author":"Inzucchi","year":"2017","journal-title":"Diabetologia"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Dowling, R.J., Goodwin, P.J., and Stambolic, V. (2011). Understanding the benefit of metformin use in cancer treatment. BMC Med., 9.","DOI":"10.1186\/1741-7015-9-33"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1136\/bmj.38415.708634.F7","article-title":"Metformin and reduced risk of cancer in diabetic patients","volume":"330","author":"Evans","year":"2005","journal-title":"BMJ"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1158\/2159-8290.CD-12-0263","article-title":"Investigating metformin for cancer prevention and treatment: The end of the beginning","volume":"2","author":"Pollak","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.2337\/dc09-1791","article-title":"Long-term metformin use is associated with decreased risk of breast cancer","volume":"33","author":"Bodmer","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.cllc.2011.10.002","article-title":"Antidiabetes drugs correlate with decreased risk of lung cancer: A population-based observation in Taiwan","volume":"13","author":"Lai","year":"2012","journal-title":"Clin. Lung Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lee, M.S., Hsu, C.C., Wahlqvist, M.L., Tsai, H.N., Chang, Y.H., and Huang, Y.C. (2011). Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: A representative population prospective cohort study of 800,000 individuals. BMC Cancer, 11.","DOI":"10.1186\/1471-2407-11-20"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.2147\/CMAR.S200059","article-title":"The beneficial effects of metformin on cancer prevention and therapy: A comprehensive review of recent advances","volume":"11","author":"Saraei","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3783","DOI":"10.1021\/acs.molpharmaceut.5b00577","article-title":"Metformin: A Novel but Controversial Drug in Cancer Prevention and Treatment","volume":"12","author":"Sui","year":"2015","journal-title":"Mol. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"R31","DOI":"10.1530\/JME-12-0007","article-title":"Metformin in cancer: Translational challenges","volume":"48","author":"Dowling","year":"2012","journal-title":"J. Mol. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"E2091","DOI":"10.1002\/hed.24387","article-title":"Outcomes for hypopharyngeal carcinoma treated with organ-preservation therapy","volume":"38","author":"Edson","year":"2016","journal-title":"Head Neck"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.pharep.2016.04.021","article-title":"Molecular targets of metformin antitumor action","volume":"68","author":"Sosnicki","year":"2016","journal-title":"Pharm. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Tsou, Y.A., Chang, W.D., Lu, J.J., Wu, T.F., Chen, H.L., Chen, C.M., and Tsai, M.H. (2019). The effect of metformin use on hypopharyngeal squamous cell carcinoma in diabetes mellitus patients. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6083-5"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"143","DOI":"10.3389\/fphar.2019.00143","article-title":"Metformin Suppresses Hypopharyngeal Cancer Growth by Epigenetically Silencing Long Non-coding RNA SNHG7 in FaDu Cells","volume":"10","author":"Wu","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0008-6363(98)00125-4","article-title":"Arresting developments in the cardiac myocyte cell cycle: Role of cyclin-dependent kinase inhibitors","volume":"39","author":"Brooks","year":"1998","journal-title":"Cardiovasc. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"a008904","DOI":"10.1101\/cshperspect.a008904","article-title":"Signaling pathways that control cell proliferation","volume":"5","author":"Duronio","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"31055","DOI":"10.1074\/jbc.274.43.31055","article-title":"Serine phosphorylation and negative regulation of Stat3 by JNK","volume":"274","author":"Lim","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1021\/cr000241p","article-title":"MAP kinases","volume":"101","author":"Chen","year":"2001","journal-title":"Chem. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e1088","DOI":"10.1038\/cddis.2014.59","article-title":"Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling","volume":"5","author":"Feng","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.cell.2005.07.002","article-title":"Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy","volume":"122","author":"Pattingre","year":"2005","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/ncb1537","article-title":"The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis","volume":"9","author":"Liang","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nrm.2016.74","article-title":"Mechanistic insights into selective autophagy pathways: Lessons from yeast","volume":"17","author":"Farre","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nrm2239","article-title":"Self-eating and self-killing: Crosstalk between autophagy and apoptosis","volume":"8","author":"Maiuri","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5159","DOI":"10.1038\/sj.emboj.7601388","article-title":"C-terminal phosphorylation controls the stability and function of p27kip1","volume":"25","author":"Kossatz","year":"2006","journal-title":"EMBO J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"74","DOI":"10.7150\/ijbs.33787","article-title":"Metformin induces cell cycle arrest, apoptosis and autophagy through ROS\/JNK signaling pathway in human osteosarcoma","volume":"16","author":"Li","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/j.1600-065X.1994.tb00886.x","article-title":"Analysis of the role of bcl-2 in apoptosis","volume":"142","author":"Hawkins","year":"1994","journal-title":"Immunol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/978-981-15-0602-4_5","article-title":"Beclin 1, Bcl-2 and Autophagy","volume":"1206","author":"Xu","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s13046-018-0731-5","article-title":"Metformin induces autophagy and G0\/G1 phase cell cycle arrest in myeloma by targeting the AMPK\/mTORC1 and mTORC2 pathways","volume":"37","author":"Wang","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3194","DOI":"10.1002\/cam4.896","article-title":"Metformin induces degradation of mTOR protein in breast cancer cells","volume":"5","author":"Alalem","year":"2016","journal-title":"Cancer Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"111286","DOI":"10.1016\/j.biopha.2021.111286","article-title":"The effects of metformin on autophagy","volume":"137","author":"Lu","year":"2021","journal-title":"Biomed. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9715","DOI":"10.1021\/acs.jafc.5b04028","article-title":"Latifolicinin A from a Fermented Soymilk Product and the Structure-Activity Relationship of Synthetic Analogues as Inhibitors of Breast Cancer Cell Growth","volume":"63","author":"Ke","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.ejphar.2011.08.006","article-title":"CHM-1 induces apoptosis via p38-mediated upregulation of DR5 expression in human ovarian cancer SKOV3 cells","volume":"670","author":"Lee","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1002\/cbdv.200490100","article-title":"A novel carbazole derivative, BMVC: A potential antitumor agent and fluorescence marker of cancer cells","volume":"1","author":"Chang","year":"2004","journal-title":"Chem. Biodivers."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1097\/00005537-200006000-00007","article-title":"Antisense RNA to eIF4E suppresses oncogenic properties of a head and neck squamous cell carcinoma cell line","volume":"110","author":"DeFatta","year":"2000","journal-title":"Laryngoscope"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5369","DOI":"10.1038\/s41598-019-41839-1","article-title":"Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts","volume":"9","author":"Gillespie","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"117717","DOI":"10.1016\/j.lfs.2020.117717","article-title":"Anticancer mechanisms of metformin: A review of the current evidence","volume":"254","author":"Zhao","year":"2020","journal-title":"Life Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.coi.2007.05.004","article-title":"Bcl-2-regulated apoptosis: Mechanism and therapeutic potential","volume":"19","author":"Adams","year":"2007","journal-title":"Curr. Opin. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"S36","DOI":"10.1038\/ijo.2008.121","article-title":"AMP-activated protein kinase and human cancer: Cancer metabolism revisited","volume":"32","author":"Kuhajda","year":"2008","journal-title":"Int. J. Obes."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/nature07813","article-title":"AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity","volume":"458","author":"Canto","year":"2009","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.molcel.2005.03.027","article-title":"AMP-activated protein kinase induces a p53-dependent metabolic checkpoint","volume":"18","author":"Jones","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Tamargo-G\u00f3mez, I., and Mari\u00f1o, G. (2018). AMPK: Regulation of metabolic dynamics in the context of autophagy. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123812"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.cell.2007.01.006","article-title":"Another piece of the p27Kip1 puzzle","volume":"128","author":"Kaldis","year":"2007","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1038\/s41556-020-0554-4","article-title":"p27 controls Ragulator and mTOR activity in amino acid-deprived cells to regulate the autophagy-lysosomal pathway and coordinate cell cycle and cell growth","volume":"22","author":"Nowosad","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.4155\/fmc-2019-0017","article-title":"Metformin inhibits angiogenesis of endothelial progenitor cells via miR-221-mediated p27 expression and autophagy","volume":"11","author":"Ni","year":"2019","journal-title":"Future Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"223","DOI":"10.3389\/fcimb.2017.00223","article-title":"Cytolethal Distending Toxin Enhances Radiosensitivity in Prostate Cancer Cells by Regulating Autophagy","volume":"7","author":"Lin","year":"2017","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3389\/fimmu.2019.00109","article-title":"Coalescence of RAGE in Lipid Rafts in Response to Cytolethal Distending Toxin-Induced Inflammation","volume":"10","author":"Lin","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s12989-020-00362-2","article-title":"PM2.5 impairs macrophage functions to exacerbate pneumococcus-induced pulmonary pathogenesis","volume":"17","author":"Chen","year":"2020","journal-title":"Part. Fibre Toxicol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"203","DOI":"10.3389\/fcimb.2016.00203","article-title":"Statin Decreases Helicobacter pylori Burden in Macrophages by Promoting Autophagy","volume":"6","author":"Liao","year":"2017","journal-title":"Front. Cell. Infect. Microbiol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/3\/191\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:29:34Z","timestamp":1760160574000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/3\/191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,26]]},"references-count":56,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ph14030191"],"URL":"https:\/\/doi.org\/10.3390\/ph14030191","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,26]]}}}