{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:49:42Z","timestamp":1787726982428,"version":"build-2784847793"},"reference-count":106,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T00:00:00Z","timestamp":1643587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004799","name":"Australian Dental Research Foundation","doi-asserted-by":"publisher","award":["109-2021"],"award-info":[{"award-number":["109-2021"]}],"id":[{"id":"10.13039\/501100004799","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Betel quid (BQ) is a package of mixed constituents that is chewed by more than 600 million people worldwide, particularly in Asia. The formulation of BQ depends on a variety of factors but typically includes areca nut, betel leaf, and slaked lime and may or may not contain tobacco. BQ chewing is strongly associated with the development of potentially malignant and malignant diseases of the mouth such as oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC), respectively. We have shown recently that the constituents of BQ vary geographically and that the capacity to induce disease reflects the distinct chemical composition of the BQ. In this review, we examined the diverse chemical constituents of BQ and their putative role in oral carcinogenesis. Four major areca alkaloids\u2014arecoline, arecaidine, guvacoline and guvacine\u2014together with the polyphenols, were identified as being potentially involved in oral carcinogenesis. Further, we propose that fibroblast senescence, which is induced by certain BQ components, may be a key driver of tumour progression in OSMF and OSCC. Our study emphasizes that the characterization of the detrimental or protective effects of specific BQ ingredients may facilitate the development of targeted BQ formulations to prevent and\/or treat potentially malignant oral disorders and oral cancer in BQ users.<\/jats:p>","DOI":"10.3390\/ijms23031637","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T08:20:29Z","timestamp":1643617229000},"page":"1637","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Molecular Mechanisms of Malignant Transformation of Oral Submucous Fibrosis by Different Betel Quid Constituents\u2014Does Fibroblast Senescence Play a Role?"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9794-2269","authenticated-orcid":false,"given":"Pangzhen","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Agriculture and Food, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel Quan En","family":"Chua","sequence":"additional","affiliation":[{"name":"Melbourne Dental School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Dang","sequence":"additional","affiliation":[{"name":"Melbourne Dental School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashleigh","family":"Davis","sequence":"additional","affiliation":[{"name":"Melbourne Dental School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kah Wee","family":"Chong","sequence":"additional","affiliation":[{"name":"Melbourne Dental School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen S.","family":"Prime","sequence":"additional","affiliation":[{"name":"Centre for Immunology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1429-1323","authenticated-orcid":false,"given":"Nicola","family":"Cirillo","sequence":"additional","affiliation":[{"name":"Melbourne Dental School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,31]]},"reference":[{"key":"ref_1","unstructured":"International Agency for Research on Cancer (IARC) (2004). Betel-quid and areca-nut chewing and some areca-nut derived nitrosamines. IARC Monogr. Eval. Carcinog. Risks Hum., 85, 1."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e767","DOI":"10.1016\/S1470-2045(17)30460-6","article-title":"Defining a global research and policy agenda for betel quid and areca nut","volume":"18","author":"Mehrtash","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Wang, Y.-Y., Tail, Y.-H., Wang, W.-C., Chen, C.-Y., Kao, Y.-H., Chen, Y.-K., and Chen, C.-H. (2014). Malignant transformation in 5071 southern Taiwanese patients with potentially malignant oral mucosal disorders. BMC Oral Health, 14.","DOI":"10.1186\/1472-6831-14-99"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Shih, Y.-H., Wang, T.-H., Shieh, T.-M., and Tseng, Y.-H. (2019). Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20122940"},{"key":"ref_5","first-page":"399","article-title":"An update on studies on etiological factors, disease progression, and malignant transformation in oral submucous fibrosis","volume":"13","author":"Bari","year":"2017","journal-title":"J. Cancer Res. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"768","DOI":"10.25259\/IJDVL_371_20","article-title":"Oral submucous fibrosis: An overview of a challenging entity","volume":"87","author":"Gupta","year":"2021","journal-title":"Indian J. Dermatol. Venereol. Leprol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1080\/152873901753215920","article-title":"Betel quid chewing and risk of adverse birth outcomes among aborigines in eastern taiwan","volume":"64","author":"Yang","year":"2001","journal-title":"J. Toxicol. Environ. Health Part A"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-73337-0","article-title":"Distinct phenolic, alkaloid and antioxidant profile in betel quids from four regions of Indonesia","volume":"10","author":"Sari","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_9","unstructured":"Jayalakshmi, A., and Mathew, G. (1982). The Areca Nut Palm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1023\/A:1020481822492","article-title":"Radiochemical neutron activation analysis for trace elements of basic ingredients of pan","volume":"253","author":"Zaidi","year":"2002","journal-title":"J. Radioanal. Nucl. Chem."},{"key":"ref_11","first-page":"26","article-title":"Traditions in oral hygiene: Chewing of betel (Piper betle L.) leaves","volume":"92","author":"Bissa","year":"2007","journal-title":"Curr. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1177\/070674377902400517","article-title":"Arecaidinism: Betel Chewing in Transcultural Perspective","volume":"24","year":"1979","journal-title":"Can. J. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s41649-017-0028-6","article-title":"A Scientific and Socioeconomic Review of Betel Nut Use in Taiwan with Bioethical Reflections","volume":"9","author":"Tham","year":"2017","journal-title":"Asian Bioeth. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/S1470-2045(03)01229-4","article-title":"Betel quid and areca nut are carcinogenic without tobacco","volume":"4","author":"Sharma","year":"2003","journal-title":"Lancet Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1080\/13556210120091509","article-title":"Areca nut-abuse liability, dependence and public health","volume":"7","author":"Winstock","year":"2002","journal-title":"Addict. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"189","DOI":"10.5539\/gjhs.v6n2p189","article-title":"Betel Nut Usage Is a Major Risk Factor for Coronary Artery Disease","volume":"6","author":"Khan","year":"2013","journal-title":"Glob. J. Health Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1007\/s11255-018-1819-8","article-title":"Betel nut chewing and the risk of chronic kidney disease: Evidence from a meta-analysis","volume":"50","author":"Wang","year":"2018","journal-title":"Int. Urol. Nephrol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1097\/01.md.0000126971.80227.a4","article-title":"Habitual Betel Quid Chewing and Risk for Hepatocellular Carcinoma Complicating Cirrhosis","volume":"83","author":"Tsai","year":"2004","journal-title":"Medicine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1111\/jop.12581","article-title":"Oral submucous fibrosis: An update on current theories of pathogenesis","volume":"46","author":"Arakeri","year":"2017","journal-title":"J. Oral Pathol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1080\/13556210120091482","article-title":"The oral health consequences of chewing areca nut","volume":"7","author":"Trivedy","year":"2002","journal-title":"Addict. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16879","DOI":"10.18632\/oncotarget.7621","article-title":"Areca nut components stimulate ADAM17, IL-1\u03b1, PGE2 and 8-isoprostane production in oral keratinocyte: Role of reactive oxygen species, EGF and JAK signaling","volume":"7","author":"Chang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_22","first-page":"400","article-title":"University of Hawai\u2019i Cancer Center connection: Areca (betel) nut consumption: An underappreciated cause of cancer","volume":"73","author":"Franke","year":"2014","journal-title":"Hawai\u2019i J. Med. Public Health A J. Asia Pac. Med. Public Health"},{"key":"ref_23","first-page":"E58","article-title":"Oral pre-malignant and malignant lesion detection among indonesian; the prevalence and risk factors","volume":"39","author":"Sari","year":"2017","journal-title":"Head Neck"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1021\/acs.jafc.6b05140","article-title":"Analysis of Alkaloids in Areca Nut-Containing Products by Liquid Chromatography\u2013Tandem Mass Spectrometry","volume":"65","author":"Jain","year":"2017","journal-title":"J. Agric. Food Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.fct.2015.03.012","article-title":"Composition of betel specific chemicals in saliva during betel chewing for the identification of biomarkers","volume":"80","author":"Franke","year":"2015","journal-title":"Food Chem. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"104276","DOI":"10.1016\/j.fitote.2019.104276","article-title":"Two new alkaloids isolated from traditional Chinese medicine Binglang the fruit of Areca catechu","volume":"138","author":"Cao","year":"2019","journal-title":"Fitoterapia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.phytochem.2016.02.002","article-title":"Developmental patterning and segregation of alkaloids in areca nut (seed of Areca catechu) revealed by magnetic resonance and mass spectrometry imaging","volume":"125","author":"Srimany","year":"2016","journal-title":"Phytochemistry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1080\/01635588309513783","article-title":"Correlation of mutagenicity and tumorigenicity of betel quid and its ingredients","volume":"5","author":"Shirname","year":"1983","journal-title":"Nutr. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1255\/ejms.1245","article-title":"A Preliminary Study of Arecoline and Guvacoline Presence in the Saliva of a \u201cBetel-Quid\u201d Chewer Using Liquid-Chromatography Ion Trap Mass Spectrometry","volume":"19","author":"Kadi","year":"2013","journal-title":"Eur. J. Mass Spectrom."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1080\/10286020.2017.1307187","article-title":"Three new areca alkaloids from the nuts of Areca catechu","volume":"19","author":"Tang","year":"2017","journal-title":"J. Asian Nat. Prod. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1080\/13556210120091455","article-title":"Chemical and analytical aspects of areca nut","volume":"7","author":"Lord","year":"2002","journal-title":"Addict. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"195","DOI":"10.4103\/2231-4040.165022","article-title":"Detection of arecoline by simple high-performance thin-layer chromatographic method in Indian nontobacco pan masala","volume":"6","author":"Sur","year":"2015","journal-title":"J. Adv. Pharm. Technol. Res."},{"key":"ref_33","first-page":"1292","article-title":"On the pharmacology of the active substances of betel. 1. Central effect of arecoline","volume":"17","author":"Nieschulz","year":"1967","journal-title":"Arzneimittelforschung"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"272","DOI":"10.2174\/1574892813666180227103147","article-title":"Oral Submucous Fibrosis as an Overhealing Wound: Implications in Malignant Transformation","volume":"13","author":"Sharma","year":"2018","journal-title":"Recent Patents Anti-Cancer Drug Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1111\/j.1600-0765.2008.01176.x","article-title":"Regulation of oxidative-stress responsive genes by arecoline in human keratinocytes","volume":"44","author":"Thangjam","year":"2009","journal-title":"J. Periodontal Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.jfma.2017.07.003","article-title":"Arecoline activates latent transforming growth factor \u03b21 via mitochondrial reactive oxygen species in buccal fibroblasts: Suppression by epigallocatechin-3-gallate","volume":"117","author":"Hsieh","year":"2018","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"41","DOI":"10.4103\/jomfp.JOMFP_214_16","article-title":"Oral submucous fibrosis: A quantitative assessment of serum malondialdehyde, superoxide dismutase and correlation with clinical staging","volume":"21","author":"Bale","year":"2017","journal-title":"J. Oral Maxillofac. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.4103\/jcar.JCar_24_20","article-title":"Understanding the molecular mechanism associated with reversal of oral submucous fibrosis targeting hydroxylysine aldehyde-derived collagen cross-links","volume":"20","author":"Radhakrishnan","year":"2021","journal-title":"J. Carcinog."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/j.2041-1626.2011.00055.x","article-title":"Relationship between thickness of fibrosis and epithelial dysplasia in oral submucous fibrosis","volume":"2","author":"Jayasooriya","year":"2011","journal-title":"J. Investig. Clin. Dent."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/S1368-8375(01)00003-3","article-title":"Role of areca nut in betel quid-associated chemical carcinogenesis: Current awareness and future perspectives","volume":"37","author":"Jeng","year":"2001","journal-title":"Oral Oncol."},{"key":"ref_41","first-page":"354","article-title":"Cellular senescence: A link between cancer and age-related degenerative disease?","volume":"21","author":"Campisi","year":"2011","journal-title":"Semin. Cancer Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1111\/j.1600-0714.2007.00625.x","article-title":"Upregulation of HIF-1\u03b1 in malignant transformation of oral submucous fibrosis","volume":"37","author":"Tilakaratne","year":"2008","journal-title":"J. Oral Pathol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1093\/carcin\/6.2.295","article-title":"Tobacco-specific and betel nut-specific N-nitroso compounds: Occurrence in saliva and urine of betel quid chewers and formation in vitro by nitrosation of betel quid","volume":"6","author":"Nair","year":"1985","journal-title":"Carcinogenesis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s11912-019-0800-8","article-title":"How Each Component of Betel Quid Is Involved in Oral Carcinogenesis: Mutual Interactions and Synergistic Effects with Other Carcinogens\u2014A Review Article","volume":"21","author":"Islam","year":"2019","journal-title":"Curr. Oncol. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e2017009","DOI":"10.4178\/epih.e2017009","article-title":"Smokeless tobacco (paan and gutkha) consumption, prevalence, and contribution to oral cancer","volume":"39","author":"Niaz","year":"2017","journal-title":"Epidemiol. Health"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Sharan, R.N., Mehrotra, R., Choudhury, Y., and Asotra, K. (2012). Association of Betel Nut with Carcinogenesis: Revisit with a Clinical Perspective. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042759"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0003-9969(86)90112-3","article-title":"Stimulation of human buccal mucosa fibroblasts in vitro by betel-nut alkaloids","volume":"31","author":"Harvey","year":"1986","journal-title":"Arch. Oral Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.31557\/APJCP.2020.21.4.1143","article-title":"In vitro Quantification of Collagen and Snail1 Gene Expression in Experimentally Induced Fibrosis by Arecoline and Commercial Smokeless Tobacco Products","volume":"21","author":"Krishnakumar","year":"2020","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1111\/j.1600-0714.2009.00758.x","article-title":"Arecoline and oral keratinocytes may affect the collagen metabolism of fibroblasts","volume":"38","author":"Xia","year":"2009","journal-title":"J. Oral Pathol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1111\/j.1600-0714.1996.tb00281.x","article-title":"Inhibition of the migration, attachment, spreading, growth and collagen synthesis of human gingival fibroblasts by arecoline, a major areca alkaloid, in vitro","volume":"25","author":"Jeng","year":"1996","journal-title":"J. Oral Pathol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1093\/mutage\/geh036","article-title":"Alert for an epidemic of oral cancer due to use of the betel quid substitutes gutkha and pan masala: A review of agents and causative mechanisms","volume":"19","author":"Nair","year":"2004","journal-title":"Mutagenesis"},{"key":"ref_52","first-page":"5294","article-title":"Cytotoxic and genotoxic effects of areca nut-related compounds in cultured human buccal epithelial cells","volume":"49","author":"Sundqvist","year":"1989","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.bjoms.2012.08.014","article-title":"Oral submucous fibrosis: An overview of the aetiology, pathogenesis, classification, and principles of management","volume":"51","author":"Arakeri","year":"2013","journal-title":"Br. J. Oral Maxillofac. Surg."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1093\/carcin\/22.9.1527","article-title":"Areca nut extract and arecoline induced the cell cycle arrest but not apoptosis of cultured oral KB epithelial cells: Association of glutathione, reactive oxygen species and mitochondrial membrane potential","volume":"22","author":"Chang","year":"2001","journal-title":"Carcinogenesis"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.3892\/or.2015.3909","article-title":"miR-203 inhibits arecoline-induced epithelial-mesenchymal transition by regulating secreted frizzled-related protein 4 and transmembrane-4 L six family member 1 in oral submucous fibrosis","volume":"33","author":"Zheng","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Cheng, R.-H., Wang, Y.-P., Chang, J., Pan, Y.-H., Chang, M.-C., and Jeng, J.-H. (2020). Genetic Susceptibility and Protein Expression of Extracellular Matrix Turnover-Related Genes in Oral Submucous Fibrosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218104"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/0140-6736(92)92109-S","article-title":"Slaked lime and betel nut cancer in Papua New Guinea","volume":"340","author":"Thomas","year":"1992","journal-title":"Lancet"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.mehy.2013.02.025","article-title":"Why only areca nut chewing cannot cause oral submucous fibrosis?","volume":"81","author":"Sarode","year":"2013","journal-title":"Med. Hypotheses"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.bbamcr.2010.01.003","article-title":"The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity","volume":"1803","author":"Brew","year":"2010","journal-title":"Biochim. Biophys. Acta BBA Mol. Cell Res."},{"key":"ref_60","unstructured":"Roy, D., and Dorak, M.T. (2021). Betel Nut and Susceptibility to Cancer. Environmental Factors, Genes, and the Development of Human Cancers, Springer."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3904098","DOI":"10.1155\/2017\/3904098","article-title":"Adverse Health Effects of Betel Quid and the Risk of Oral and Pharyngeal Cancers","volume":"2017","author":"Chen","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"261","DOI":"10.4103\/ijdr.IJDR_431_17","article-title":"Quantitative analysis of copper levels in areca nut plantation area\u2014A role in increasing prevalence of oral submucous fibrosis: An In vitro study","volume":"30","author":"Alexander","year":"2019","journal-title":"Indian J. Dent. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.bcp.2015.07.017","article-title":"Pro-oxidant activity of polyphenols and its implication on cancer chemoprevention and chemotherapy","volume":"98","author":"Auger","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.jdent.2009.02.003","article-title":"Polyphenols, oral health and disease: A review","volume":"37","author":"Petti","year":"2009","journal-title":"J. Dent."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3892\/ijfn.2020.9","article-title":"Polyphenols in cancer prevention: New insights (Review)","volume":"1","author":"Briguglio","year":"2020","journal-title":"Int. J. Funct. Nutr."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"467305","DOI":"10.1155\/2011\/467305","article-title":"Research Strategies in the Study of the Pro-Oxidant Nature of Polyphenol Nutraceuticals","volume":"2011","author":"Babich","year":"2011","journal-title":"J. Toxicol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1111\/j.1600-0714.2007.00588.x","article-title":"Epigallocatechin-3-gallate inhibits the invasion of humanoral cancer cells and decreases the productions of matrixmetalloproteinases and urokinase-plasminogen activator","volume":"36","author":"Ho","year":"2007","journal-title":"J. Oral Pathol. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1002\/(SICI)1097-0347(199809)20:6<528::AID-HED7>3.0.CO;2-3","article-title":"Green tea regulates cell cycle progression in oralleukoplakia","volume":"20","author":"Khafif","year":"1998","journal-title":"Head Neck"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1111\/jop.12914","article-title":"Functional and molecular effects of a green tea constituent on oral cancer cells","volume":"48","author":"Belobrov","year":"2019","journal-title":"J. Oral Pathol. Med."},{"key":"ref_70","first-page":"276","article-title":"A review on Piper betle L.: Nature\u2019s promising medicinal reservoir","volume":"1","author":"Rekha","year":"2014","journal-title":"Am. J. Ethnomed."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2932","DOI":"10.1016\/j.bmc.2007.12.052","article-title":"Inhibitory property of the Piper betel phenolics against photosensitization-induced biological damages","volume":"16","author":"Mula","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_72","first-page":"2991","article-title":"Piper betle L.: A review on its ethnobotany, phytochemistry, pharmacological profile and profiling by new hyphenated technique DART-MS (Direct Analysis in Real Time Mass Spectrometry)","volume":"4","author":"Nagori","year":"2011","journal-title":"J. Pharm. Res."},{"key":"ref_73","first-page":"147","article-title":"Golden heart of the nature: Piper betle L","volume":"1","author":"Pradhan","year":"2013","journal-title":"J. Pharm. Phytochem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1158\/1055-9965.EPI-07-0168","article-title":"Flavonoids and the Risk of Oral and Pharyngeal Cancer: A Case-Control Study from Italy","volume":"16","author":"Rossi","year":"2007","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2564","DOI":"10.3390\/nu5072564","article-title":"Chemopreventive Potential of Flavonoids in Oral Squamous Cell Carcinoma in Human Studies","volume":"5","author":"Iriti","year":"2013","journal-title":"Nutrients"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1093\/ecam\/nen011","article-title":"Inhibition of Cell Proliferation and MAP Kinase and Akt Pathways in Oral Squamous Cell Carcinoma by Genistein and Biochanin A","volume":"7","author":"Johnson","year":"2010","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.ejphar.2011.09.179","article-title":"Chemopreventive potential of apigenin in 7,12-dimethylbenz(a)anthracene induced experimental oral carcinogenesis","volume":"670","author":"Silvan","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_78","first-page":"262","article-title":"Modulation of glutathione and antioxidant enzymes by Ocimum sanctum and its role in protection against radiation injury","volume":"37","author":"Devi","year":"1999","journal-title":"Indian J. Exp. Boil."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/BF02893064","article-title":"Effect of ocimum flavonoids as a radioprotector on the erythrocyte antioxidants in oral cancer","volume":"20","author":"Reshma","year":"2005","journal-title":"Indian J. Clin. Biochem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.3109\/13880207209068238","article-title":"Further Associations of Plant Tannins and Human Cancer","volume":"12","author":"Morton","year":"1972","journal-title":"Q. J. Crude Drug Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1093\/carcin\/7.1.37","article-title":"Study of the genotoxicity of the total aqueous extract of betel nut and its tannin","volume":"7","author":"Panigrahi","year":"1986","journal-title":"Carcinogenesis"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"112799","DOI":"10.1016\/j.phytochem.2021.112799","article-title":"An overview on the role of plant-derived tannins for the treatment of lung cancer","volume":"188","author":"Rajasekar","year":"2021","journal-title":"Phytochemistry"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s40495-020-00211-y","article-title":"Tannic Acid: Specific Form of Tannins in Cancer Chemoprevention and Therapy-Old and New Applications","volume":"6","author":"Szaefer","year":"2020","journal-title":"Curr. Pharmacol. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"43","DOI":"10.11620\/IJOB.2019.44.2.43","article-title":"Tannic acid-induced apoptosis in FaDu hypopharyngeal squamous cell carcinoma","volume":"44","author":"Ta","year":"2019","journal-title":"Int. J. Oral Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.3892\/ijo.2015.3098","article-title":"Tannic acid inhibits the Jak2\/STAT3 pathway and induces G1\/S arrest and mitochondrial apoptosis in YD-38 gingival cancer cells","volume":"47","author":"Darvin","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1615\/JEnvironPatholToxicolOncol.2016014024","article-title":"Molecular Pathology of Malignant Transformation of Oral Submucous Fibrosis","volume":"35","author":"Chattopadhyay","year":"2016","journal-title":"J. Environ. Pathol. Toxicol. Oncol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.mrgentox.2012.07.001","article-title":"Assessment of the mutagenic potential of arecoline in gpt delta transgenic mice","volume":"748","author":"Wu","year":"2012","journal-title":"Mutat. Res. Toxicol. Environ. Mutagen."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.mrfmmm.2006.01.005","article-title":"Genetic damage in cultured human keratinocytes stressed by long-term exposure to areca nut extracts","volume":"599","author":"Lai","year":"2006","journal-title":"Mutat. Res. Mol. Mech. Mutagen."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.2353\/ajpath.2006.051027","article-title":"A 318 keratinocyte hypermotility\/growth-arrest response involving laminin 5 and p16INK4A activated in 319 wound healing and senescence","volume":"168","author":"Natarajan","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41368-020-00090-5","article-title":"Loss of oral mucosal stem cell markers in oral submucous fibrosis and their reactivation in malignant transformation","volume":"12","author":"Sharma","year":"2020","journal-title":"Int. J. Oral Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3153","DOI":"10.1002\/hed.26805","article-title":"Emerging role of cellular senescence in the pathogenesis of oral submucous fibrosis and its malignant transformation","volume":"43","author":"Sharma","year":"2021","journal-title":"Head Neck"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/jop.12370","article-title":"Areca nut alkaloids induce irreparable DNA damage and senescence in fibroblasts and may create a favourable environment for tumour progression","volume":"45","author":"Rehman","year":"2015","journal-title":"J. Oral Pathol. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1002\/path.2839","article-title":"Senescent mesenchymal cells accumulate in human fibrosis by a telomere-independent mechanism and ameliorate fibrosis through matrix metalloproteinases","volume":"223","author":"Pitiyage","year":"2011","journal-title":"J. Pathol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/jop.12456","article-title":"Fibroblast activation and senescence in oral cancer","volume":"46","author":"Prime","year":"2016","journal-title":"J. Oral Pathol. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1002\/path.2841","article-title":"Fibroblast gene expression profile reflects the stage of tumour progression in oral squamous cell carcinoma","volume":"223","author":"Lim","year":"2011","journal-title":"J. Pathol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1093\/carcin\/bgt035","article-title":"Progression of genotype-specific oral cancer leads to senescence of cancer-associated fibroblasts and is mediated by oxidative stress and TGF-\u03b2","volume":"34","author":"Hassona","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1038\/bjc.2014.438","article-title":"Senescent cancer-associated fibroblasts secrete active MMP-2 that promotes keratinocyte dis-cohesion and invasion","volume":"111","author":"Hassona","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1093\/carcin\/bgw113","article-title":"Cancer-associated fibroblasts regulate keratinocyte cell\u2013cell adhesion via TGF-\u03b2-dependent pathways in genotype-specific oral cancer","volume":"38","author":"Cirillo","year":"2017","journal-title":"Carcinogenesis"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.jdsr.2020.07.002","article-title":"Signaling pathways promoting epithelial mesenchymal transition in oral submucous fibrosis and oral squamous cell carcinoma","volume":"56","author":"Shetty","year":"2020","journal-title":"Jpn. Dent. Sci. Rev."},{"key":"ref_100","first-page":"1596","article-title":"Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia","volume":"63","author":"Holst","year":"2003","journal-title":"Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1038\/emboj.2011.69","article-title":"p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype","volume":"30","author":"Freund","year":"2011","journal-title":"EMBO J."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2002611","DOI":"10.1002\/advs.202002611","article-title":"Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities","volume":"7","author":"Song","year":"2020","journal-title":"Adv. Sci."},{"key":"ref_103","first-page":"554","article-title":"B17. Senolytics in Idiopathic Pulmonary Fibrosis: Preliminary Results from a First-in-Human, Open-Label, Pilot Study","volume":"40","author":"Nambiar","year":"2019","journal-title":"Adv. Ild Ther."},{"key":"ref_104","first-page":"41","article-title":"Turmeric in the management of oral submucous fibrosis\u2014A systematic review and meta-analysis","volume":"14","author":"Ingle","year":"2020","journal-title":"Int. J. Health Sci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1111\/odi.13544","article-title":"Herbal derivatives in the management of mouth opening in oral submucous fibrosis\u2014A network meta-analysis","volume":"27","author":"Kashyap","year":"2021","journal-title":"Oral Dis."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.oraloncology.2018.10.021","article-title":"Malignant transformation to oral cancer by subtype of oral potentially malignant disorder: A prospective cohort study of Taiwanese nationwide oral cancer screening program","volume":"87","author":"Chuang","year":"2018","journal-title":"Oral Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1637\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:11:46Z","timestamp":1760134306000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1637"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,31]]},"references-count":106,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23031637"],"URL":"https:\/\/doi.org\/10.3390\/ijms23031637","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,31]]}}}