{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T20:38:47Z","timestamp":1790455127015,"version":"4.1.0"},"reference-count":149,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T00:00:00Z","timestamp":1676937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinics and Practice"],"abstract":"<jats:p>Oral cancers (OC) are among the most frequent malignancies encountered in Southeast Asia, primarily due to the prevalent habit of betel quid (BQ) and smokeless tobacco use in this region. Areca nut (AN), the primary ingredient in BQ, contains several alkaloids, including arecoline, arecaidine, guvacoline, and guvacine. These have been associated with both the AN abuse liability and carcinogenicity. Additionally, variations in AN alkaloid levels could lead to differences in the addictiveness and carcinogenic potential across various AN-containing products. Recent studies based on animal models and in vitro experiments show cellular and molecular effects induced by AN. These comprise promoting epithelial-mesenchymal transition, autophagy initiation, tissue hypoxia, genotoxicity, cytotoxicity, and cell death. Further, clinical research endorses these undesired harmful effects in humans. Oral submucosal fibrosis, a potentially malignant disease of the oral cavity, is predominantly reported from the geographical areas of the globe where AN is habitually chewed. OC in chronic AN users presents a more aggressive phenotype, such as resistance to anti-cancer drugs. The available evidence on the carcinogenicity of AN based on the findings reported in the recently published experimental studies is discussed in the present review.<\/jats:p>","DOI":"10.3390\/clinpract13020030","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T03:04:12Z","timestamp":1676948652000},"page":"326-346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Carcinogenic Effects of Areca Nut and Its Metabolites: A Review of the Experimental Evidence"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5768-1351","authenticated-orcid":false,"given":"Kalpani","family":"Senevirathna","sequence":"first","affiliation":[{"name":"Centre for Research in Oral Cancer (CROC), Faculty of Dental Sciences, University of Peradeniya, Peradeniya 20400, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2734-8248","authenticated-orcid":false,"given":"Roshan","family":"Pradeep","sequence":"additional","affiliation":[{"name":"Centre for Research in Oral Cancer (CROC), Faculty of Dental Sciences, University of Peradeniya, Peradeniya 20400, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5144-5550","authenticated-orcid":false,"given":"Yovanthi Anurangi","family":"Jayasinghe","sequence":"additional","affiliation":[{"name":"Centre for Research in Oral Cancer (CROC), Faculty of Dental Sciences, University of Peradeniya, Peradeniya 20400, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4582-4006","authenticated-orcid":false,"given":"Shalindu Malshan","family":"Jayawickrama","sequence":"additional","affiliation":[{"name":"Centre for Research in Oral Cancer (CROC), Faculty of Dental Sciences, University of Peradeniya, Peradeniya 20400, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5506-0981","authenticated-orcid":false,"given":"Rasika","family":"Illeperuma","sequence":"additional","affiliation":[{"name":"Centre for Research in Oral Cancer (CROC), Faculty of Dental Sciences, University of Peradeniya, Peradeniya 20400, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2103-0746","authenticated-orcid":false,"given":"Saman","family":"Warnakulasuriya","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry, Oral and Craniofacial Sciences, King\u2019s College, London SE1 9RA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8054-4301","authenticated-orcid":false,"given":"Ruwan Duminda","family":"Jayasinghe","sequence":"additional","affiliation":[{"name":"Centre for Research in Oral Cancer (CROC), Faculty of Dental Sciences, University of Peradeniya, Peradeniya 20400, Sri Lanka"},{"name":"Department of Oral Medicine and Periodontology, Faculty of Dental Sciences, University of Peradeniya, Peradeniya 20400, Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.2041-1626.2012.00130.x","article-title":"Oral lichenoid contact lesions induced by areca nut and betel quid chewing: A mini review","volume":"3","author":"Reichart","year":"2012","journal-title":"J. Investig. Clin. Dent."},{"key":"ref_2","unstructured":"IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2004). Betel-quid and areca-nut chewing and some areca-nut derived nitrosamines. IARC Monogr. Eval. Carcinog. Risks Hum., 85, 1."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1080\/13556210020091437","article-title":"Global Epidemiology of Areca Nut Usage","volume":"7","author":"Gupta","year":"2002","journal-title":"Addict. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.oraloncology.2006.08.010","article-title":"A review of Betel quid chewing, oral cancer and precancer in Mainland China","volume":"43","author":"Zhang","year":"2007","journal-title":"Oral Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1111\/j.1349-7006.2008.00863.x","article-title":"Head and neck cancer in the betel quid chewing area: Recent advances in molecular carcinogenesis","volume":"99","author":"Chen","year":"2008","journal-title":"Cancer Sci."},{"key":"ref_6","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_7","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_8","doi-asserted-by":"crossref","unstructured":"Gupta, B., and Johnson, N.W. (2014). Systematic Review and meta-analysis of association of Smokeless Tobacco and of betel quid without tobacco with incidence of oral cancer in South Asia and the Pacific. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0113385"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.oraloncology.2014.04.010","article-title":"Clinical evidence of field cancerization in patients with oral cavity cancer in a betel quid chewing area","volume":"50","author":"Liao","year":"2014","journal-title":"Oral Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3","DOI":"10.4103\/0971-5851.133702","article-title":"A review of the systemic adverse effects of areca nut or betel nut","volume":"35","author":"Garg","year":"2014","journal-title":"Indian J. Med. Paediatr. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1093\/jat\/bkv077","article-title":"Quantification of salivary arecoline, arecaidine and n-methylnipecotic acid levels in volunteers by liquid chromatography-tandem mass spectrometry","volume":"39","author":"Lee","year":"2015","journal-title":"J. Anal. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1111\/j.1600-0714.2009.00881.x","article-title":"Salivary arecoline levels during areca nut chewing in human volunteers","volume":"39","author":"Cox","year":"2010","journal-title":"J. Oral Pathol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"379","DOI":"10.4103\/0973-1482.148729","article-title":"Evaluation of transforming growth factor beta1 gene in oral submucous fibrosis induced in Sprague-Dawley rats by injections of areca nut and Pan Masala (commercial areca nut product) extracts","volume":"12","author":"Kamath","year":"2016","journal-title":"J. Cancer Res. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Chiang, M.-H., Chen, P.-H., Chen, Y.-K., Chen, C.-H., Ho, M.-L., and Wang, Y.-H. (2016). Characterization of a novel dermal fibrosis model induced by areca nut extract that mimics oral submucous fibrosis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166454"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1021\/acs.jproteome.6b00138","article-title":"Proteomics analysis reveals involvement of KRT17 in areca nut-induced oral carcinogenesis","volume":"15","author":"Chiang","year":"2016","journal-title":"J. Proteome Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5787","DOI":"10.1021\/acs.jafc.5b01351","article-title":"Fibrotic effects of arecoline n-oxide in oral potentially malignant disorders","volume":"63","author":"Kuo","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s007840000085","article-title":"Cytotoxicity and arecoline mechanisms in human gingival fibroblasts in vitro","volume":"5","author":"Chang","year":"2001","journal-title":"Clin. Oral Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/j.1600-0714.1999.tb01998.x","article-title":"Effects of areca nut, inflorescence piper betle extracts and arecoline on cytotoxicity, total and unscheduled DNA synthesis in cultured gingival keratinocytes","volume":"28","author":"Jeng","year":"2007","journal-title":"J. Oral Pathol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.tox.2008.05.007","article-title":"Arecoline, a major alkaloid of areca nut, inhibits p53, represses DNA repair, and triggers DNA damage response in human epithelial cells","volume":"249","author":"Tsai","year":"2008","journal-title":"Toxicology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1007\/BF00398180","article-title":"Aqueous extract of betel-nut of north-east india induces DNA-strand breaks and enhances rate of cell proliferation in vitro","volume":"114","author":"Wary","year":"1988","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0165-1218(10)80007-2","article-title":"Study of unscheduled DNA synthesis following exposure of human cells to arecoline and extracts of betel nut in vitro","volume":"278","author":"Sharan","year":"1992","journal-title":"Mutat. Res. Genet. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1093\/carcin\/bgi357","article-title":"Ripe areca nut extract induces G 1 phase arrests and senescence-associated phenotypes in normal human oral keratinocyte","volume":"27","author":"Lu","year":"2006","journal-title":"Carcinogenesis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1002\/em.20463","article-title":"Areca nut-induced micronuclei and cytokinesis failure in Chinese hamster ovary cells is related to reactive oxygen species production and actin filament deregulation","volume":"50","author":"Lin","year":"2009","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1093\/toxsci\/kfm201","article-title":"Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling","volume":"100","author":"Chiang","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_25","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. Fundam. Mol. Mech. Mutagen."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1002\/ijc.29636","article-title":"Areca nut exposure increases secretion of tumor-promoting cytokines in gingival fibroblasts that trigger dna damage in oral keratinocytes","volume":"137","author":"Illeperuma","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"50676","DOI":"10.1074\/jbc.M404465200","article-title":"The induction of prostaglandin E2 production, interleukin-6 production, cell cycle arrest, and cytotoxicity in primary oral keratinocytes and KB cancer cells by areca nut ingredients is differentially regulated by MEK\/Erk Activation","volume":"279","author":"Chang","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chang, M.-C., Chen, Y.-J., Chang, H.-H., Chan, C.-P., Yeh, C.-Y., Wang, Y.-L., Cheng, R.-H., Hahn, L.-J., and Jeng, J.-H. (2014). Areca nut components affect COX-2, cyclin B1\/cdc25c and keratin expression, PGE2 production in keratinocyte is related to reactive oxygen species, CYP1A1, SRC, EGFR and Ras Signaling. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101959"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.jfma.2015.05.009","article-title":"Elevation of Twist expression by arecoline contributes to the pathogenesis of oral submucous fibrosis","volume":"115","author":"Lee","year":"2016","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Pant, I., Kumar, N., Khan, I., Rao, S.G., and Kondaiah, P. (2015). Role of areca nut induced TGF-\u03b2 and epithelial-mesenchymal interaction in the pathogenesis of oral submucous fibrosis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129252"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0304-3835(84)90153-8","article-title":"Induction of in vivo sister chromatid exchanges by arecaidine, a betel nut alkaloid, in mouse bone-marrow cells","volume":"23","author":"Panigrahi","year":"1984","journal-title":"Cancer Lett."},{"key":"ref_32","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. Genet. Toxicol. Environ. Mutagen."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tox.2007.09.003","article-title":"Arecoline-induced growth arrest and P21WAF1 expression are dependent on p53 in rat hepatocytes","volume":"243","author":"Chou","year":"2008","journal-title":"Toxicology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/BF01208617","article-title":"In vitro genotoxic effects of areca nut extract and Arecoline","volume":"118","author":"Dave","year":"1992","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0021-9673(01)89702-8","article-title":"High-performance liquid chromatographic determination of the alkaloids in betel nut","volume":"475","author":"Huang","year":"1989","journal-title":"J. Chromatogr. A"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.oooo.2016.04.003","article-title":"Oral submucous fibrosis: A historical perspective and a review on etiology and pathogenesis","volume":"122","author":"Tilakaratne","year":"2016","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1093\/occmed\/kqs011","article-title":"IARC monographs on the evaluation of carcinogenic risks to humans. volume 99: Some aromatic amines, organic dyes, and related exposures. International Agency for Research on Cancer","volume":"62","author":"Trakoli","year":"2012","journal-title":"Occup. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1034\/j.1600-0714.2003.00004.x","article-title":"The up-regulation of cyclooxygenase-2 expression in human buccal mucosal fibroblasts by Arecoline: A possible role in the pathogenesis of oral submucous fibrosis","volume":"32","author":"Tsai","year":"2003","journal-title":"J. Oral Pathol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0009-2797(87)90095-0","article-title":"Formation of reactive oxygen species and of 8-hydroxydeoxyguanosine in DNA in vitro with betel quid ingredients","volume":"63","author":"Nair","year":"1987","journal-title":"Chem. Biol. Interact."},{"key":"ref_40","first-page":"467","article-title":"3-(Methylnitrosamino) propionitrile: Occurrence in saliva of betel quid chewers, carcinogenicity, and DNA methylation in F344 rats","volume":"47","author":"Prokopczyk","year":"1987","journal-title":"Cancer Res."},{"key":"ref_41","first-page":"5294","article-title":"Cytotoxic and genotoxic effects of areca nut-related compounds in cultured human buccal epithelial cells","volume":"49","author":"Moon","year":"1989","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1600-0714.1996.tb00194.x","article-title":"Minimal arecaidine concentrations showing a promotion effect during DMBA-induced hamster cheek pouch carcinogenesis","volume":"25","author":"Lin","year":"1996","journal-title":"J. Oral Pathol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.cbi.2009.10.005","article-title":"Co-treating with Arecoline and 4-Nitroquinoline 1-oxide to establish a mouse model mimicking oral tumorigenesis","volume":"183","author":"Chang","year":"2010","journal-title":"Chem. Biol. Interact."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.jfma.2015.01.004","article-title":"Cytotoxicity and transformation of C3H10T1\/2 cells induced by areca nut components","volume":"115","author":"Yeh","year":"2016","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1002\/ijc.2910470315","article-title":"Cytotoxic and cytostatic effects of arecoline and sodium nitrite on human cellsin vitro","volume":"47","author":"Wary","year":"1991","journal-title":"Int. J. Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.oraloncology.2006.11.018","article-title":"Up-regulation of matrix metalloproteinase-8 by betel quid extract and arecoline and its role in 2D motility","volume":"43","author":"Liu","year":"2007","journal-title":"Oral Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0090-6980(02)00002-3","article-title":"The effect of betel nut extract on cell growth and prostaglandin endoperoxide synthase in human epidermoid carcinoma cells","volume":"67","author":"Yang","year":"2002","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/S1368-8375(00)00031-2","article-title":"Induction of the c-jun protooncogene expression by areca nut extract and arecoline on oral mucosal fibroblasts","volume":"36","author":"Ho","year":"2000","journal-title":"Oral Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1177\/00220345940730050501","article-title":"Genotoxic and non-genotoxic effects of betel quid ingredients on oral mucosal fibroblasts in vitro","volume":"73","author":"Jeng","year":"1994","journal-title":"J. Dent. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1034\/j.1600-0714.2003.00199.x","article-title":"Areca nut extract treatment elicits the fibroblastoid morphological changes, actin re-organization and signaling activation in oral keratinocytes","volume":"32","author":"Yang","year":"2003","journal-title":"J. Oral Pathol. Med."},{"key":"ref_51","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_52","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_53","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.tox.2005.07.026","article-title":"Prolonged exposure to arecoline arrested human KB epithelial cell growth: Regulatory mechanisms of cell cycle and apoptosis","volume":"220","author":"Lee","year":"2006","journal-title":"Toxicology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1093\/toxsci\/kfr182","article-title":"Areca nut induces mir-23a and inhibits repair of DNA double-strand breaks by targeting FANCG","volume":"123","author":"Tsai","year":"2011","journal-title":"Toxicol. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1177\/154405910808701111","article-title":"Areca-treated fibroblasts enhance tumorigenesis of oral epithelial cells","volume":"87","author":"Lu","year":"2008","journal-title":"J. Dent. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3420","DOI":"10.1021\/jf104831n","article-title":"Arecoline N-oxide: Its mutagenicity and possible role as ultimate carcinogen in areca oral carcinogenesis","volume":"59","author":"Lin","year":"2011","journal-title":"J. Agric. Food Chem."},{"key":"ref_57","first-page":"165","article-title":"Induction of mutations by different extracts of betel nut and radiation: Their implication in carcinogenesis","volume":"1","author":"Balachandran","year":"1995","journal-title":"Radiat. Res."},{"key":"ref_58","first-page":"13","article-title":"Association of betel nut with carcinogenesis","volume":"9","author":"Sharan","year":"1996","journal-title":"Cancer J."},{"key":"ref_59","first-page":"190","article-title":"Biochemical investigation of carcinogenic potency of betel nut (Kwai) of north-east India","volume":"3","author":"Sharan","year":"1994","journal-title":"Oral Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.cellsig.2012.01.008","article-title":"Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling","volume":"24","author":"Ray","year":"2012","journal-title":"Cell. Signal."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/nrd2803","article-title":"Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach?","volume":"8","author":"Trachootham","year":"2009","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.cardiores.2006.05.001","article-title":"Redox signaling in hypertension","volume":"71","author":"Paravicini","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"S18","DOI":"10.1038\/nrn1434","article-title":"Oxidative stress in neurodegeneration: Cause or consequence?","volume":"10","author":"Andersen","year":"2004","journal-title":"Nat. Med."},{"key":"ref_64","first-page":"572634","article-title":"Oxidative stress in neurodegeneration","volume":"2011","author":"Shukla","year":"2011","journal-title":"Adv. Pharmacol. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.molcel.2010.10.002","article-title":"The aging stress response","volume":"40","author":"Haigis","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1126\/science.1156906","article-title":"ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis","volume":"320","author":"Ishikawa","year":"2008","journal-title":"Science"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0027-5107(89)90197-8","article-title":"The involvement of reactive oxygen species in oral cancers of Betel Quid\/tobacco chewers","volume":"214","author":"Stich","year":"1989","journal-title":"Mutat. Res. Fundam. Mol. Mech. Mutagen."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1093\/carcin\/16.5.1195","article-title":"ortho- and meta-tyrosine formation from phenylalanine in human saliva as a marker of hydroxyl radical generation during betel quid chewing","volume":"16","author":"Nair","year":"1995","journal-title":"Carcinogenesis"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"618032","DOI":"10.1155\/2013\/618032","article-title":"Cytochrome P450 metabolism of betel quid-derived compounds: Implications for the development of prevention strategies for oral and pharyngeal cancers","volume":"2013","author":"Lin","year":"2013","journal-title":"Sci. World J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1016\/j.freeradbiomed.2010.07.017","article-title":"Arecoline, a major alkaloid of the areca nut, causes neurotoxicity through enhancement of oxidative stress and suppression of the antioxidant protective system","volume":"49","author":"Shih","year":"2010","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.oraloncology.2011.02.014","article-title":"Arecoline-mediated inhibition of AMP-activated protein kinase through reactive oxygen species is required for apoptosis induction","volume":"47","author":"Yen","year":"2011","journal-title":"Oral Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1383-5718(03)00048-2","article-title":"Genotoxic effect of raw betel-nut extract in relation to endogenous glutathione levels and its mechanism of action in mammalian cells","volume":"538","author":"Kumpawat","year":"2003","journal-title":"Mutat. Res. Genet. Toxicol. Environ. Mutagen."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.ijcard.2010.05.015","article-title":"Hemeoxygenase-1 expression in response to arecoline-induced oxidative stress in human umbilical vein endothelial cells","volume":"151","author":"Hung","year":"2011","journal-title":"Int. J. Cardiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/j.1600-0765.2008.01104.x","article-title":"Areca nut extracts increased expression of inflammatory cytokines, tumor necrosis factor-\u03b1, interleukin-1\u03b2, interleukin-6 and interleukin-8, in peripheral blood mononuclear cells","volume":"44","author":"Chang","year":"2009","journal-title":"J. Periodontal Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1902\/jop.2006.060039","article-title":"Enhancing effects of areca nut extracts on the production of interleukin-6 and interleukin-8 by peripheral blood mononuclear cells","volume":"77","author":"Chang","year":"2006","journal-title":"J. Periodontol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1111\/j.1600-0765.2006.00958.x","article-title":"Areca nut extracts-activated secretion of leukotriene B4, and phosphorylation of p38 mitogen-activated protein kinase and elevated intracellular calcium concentrations in human polymorphonuclear leukocytes","volume":"42","author":"Hung","year":"2007","journal-title":"J. Periodontal Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1902\/jop.2010.090660","article-title":"Stimulatory effects of areca nut extracts on prostaglandin E2production by human Polymorphonuclear Leukocytes","volume":"81","author":"Lai","year":"2010","journal-title":"J. Periodontol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1034\/j.1600-0714.2000.290304.x","article-title":"Oral submucous fibrosis patients have altered levels of cytokine production","volume":"29","author":"Haque","year":"2000","journal-title":"J. Oral Pathol. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1006\/cyto.1997.0342","article-title":"Immunolocalization of cytokines and growth factors in oral submucous fibrosis","volume":"10","author":"Haque","year":"1998","journal-title":"Cytokine"},{"key":"ref_80","first-page":"1369","article-title":"Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer","volume":"5","author":"Chen","year":"1999","journal-title":"Clin. Cancer Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/mc.20113","article-title":"The feasibility of monitoring NF-\u03baB associated cytokines: TNF-\u03b1, IL-1\u03b1, IL-6, and IL-8 in whole saliva for the malignant transformation of oral lichen planus","volume":"44","author":"Rhodus","year":"2005","journal-title":"Mol. Carcinog."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1002\/hed.23119","article-title":"Toxicity of areca nut ingredients: Activation of Chk1\/CHK2, induction of cell cycle arrest, and regulation of MMP-9 and TIMPs production in SAS epithelial cells","volume":"35","author":"Chang","year":"2012","journal-title":"Head Neck"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1172\/JCI31537","article-title":"A cytokine-mediated link between innate immunity, inflammation, and cancer","volume":"117","author":"Lin","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_84","first-page":"3620","article-title":"Molecular mechanisms for inflammation-promoted pathogenesis of cancer\u2014The Sixteenth International Symposium of the Sapporo Cancer Seminar","volume":"57","author":"Parsonne","year":"1997","journal-title":"Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3410\/M3-11","article-title":"Innate inflammation and cancer: Is it time for cancer prevention?","volume":"3","author":"Trinchieri","year":"2011","journal-title":"F1000 Med. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/j.1600-0757.2006.00170.x","article-title":"The roles of cyclooxygenase-2 and prostaglandin E2in periodontal disease","volume":"43","author":"Noguchi","year":"2007","journal-title":"Periodontol. 2000"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/j.1600-0757.2007.00229.x","article-title":"Control of inflammation and periodontitis","volume":"45","year":"2007","journal-title":"Periodontol. 2000"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"25","DOI":"10.4103\/0973-029X.157196","article-title":"The master switch: Comparative study of mast cell in oral epithelial dysplasia, oral submucous fibrosis and oral squamous cells carcinoma and their association with inflammation and angiogenesis","volume":"19","author":"Telagi","year":"2015","journal-title":"J. Oral Maxillofac. Pathol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/S1368-8375(03)00101-5","article-title":"Augmented mrna expression of tissue inhibitor of metalloproteinase-1 in buccal mucosal fibroblasts by arecoline and safrole as a possible pathogenesis for oral submucous fibrosis","volume":"39","author":"Shieh","year":"2003","journal-title":"Oral Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1016\/j.archoralbio.2013.05.006","article-title":"Areca nut extracts increased the expression of cyclooxygenase-2, prostaglandin E2 and interleukin-1\u03b1 in human immune cells via oxidative stress","volume":"58","author":"Chang","year":"2013","journal-title":"Arch. Oral Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/S0929-6646(10)60129-5","article-title":"Possible mechanism of betel-quid-extract-induced expression of matrix metalloproteinase-2","volume":"109","author":"Liu","year":"2010","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.3892\/ol.2017.6194","article-title":"Upregulated expression of MMP-9 in gingival epithelial cells induced by prolonged stimulation with arecoline","volume":"14","author":"Uehara","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.bbrc.2010.07.042","article-title":"Betel quid extract promotes oral cancer cell migration by activating a muscarinic M4 receptor-mediated signaling cascade involving sfks and ERK1\/2","volume":"399","author":"Chiu","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1002\/mc.22344","article-title":"Areca nut contributes to oral malignancy through facilitating the conversion of cancer stem cells","volume":"55","author":"Li","year":"2015","journal-title":"Mol. Carcinog."},{"key":"ref_95","first-page":"113","article-title":"Areca quid chewing enhances the expression of salivary matrix metalloproteinase-9","volume":"104","author":"Liu","year":"2005","journal-title":"J. Formos. Med. Assoc. Taiwan Yi Zhi"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1146\/annurev-physiol-012110-142225","article-title":"Epithelial-mesenchymal interactions in pulmonary fibrosis","volume":"73","author":"Chapman","year":"2011","journal-title":"Annu. Rev. Physiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1172\/JCI39675","article-title":"EMT: When epithelial cells decide to become mesenchymal-like cells","volume":"119","author":"Kalluri","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.cell.2009.11.007","article-title":"Epithelial-mesenchymal transitions in development and disease","volume":"139","author":"Thiery","year":"2009","journal-title":"Cell"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nrm1835","article-title":"Complex networks orchestrate epithelial\u2013mesenchymal transitions","volume":"7","author":"Thiery","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1172\/JCI38019","article-title":"Epithelial-mesenchymal transitions: The importance of changing cell state in development and disease","volume":"119","author":"Acloque","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1172\/JCI200320530","article-title":"Epithelial-mesenchymal transition and its implications for fibrosis","volume":"112","author":"Kalluri","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1172\/JCI39104","article-title":"Erratum: The basics of epithelial-mesenchymal transition","volume":"119","author":"Kalluri","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1111\/jcmm.12219","article-title":"Arecoline-induced myofibroblast transdifferentiation from human buccal mucosal fibroblasts is mediated byzeb1","volume":"18","author":"Chang","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"6721","DOI":"10.1002\/jcp.27418","article-title":"Slug mediates myofibroblastic differentiation to promote fibrogenesis in buccal mucosa","volume":"234","author":"Fang","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"208","DOI":"10.2353\/ajpath.2010.090952","article-title":"Epithelial to mesenchymal transition in gingival overgrowth","volume":"177","author":"Sume","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.oraloncology.2006.08.003","article-title":"Areca nut extract treatment down-regulates involucrin in normal human oral keratinocyte through P13K\/Akt Activation","volume":"43","author":"Tseng","year":"2007","journal-title":"Oral Oncol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/j.1600-0714.2010.00978.x","article-title":"Areca nut extract upregulates vimentin by activating PI3K\/Akt signaling in oral carcinoma","volume":"40","author":"Tseng","year":"2010","journal-title":"J. Oral Pathol. Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1111\/jop.12286","article-title":"ZEB1 as an indicator of tumor recurrence for areca quid chewing-associated oral squamous cell carcinomas","volume":"44","author":"Ho","year":"2014","journal-title":"J. Oral Pathol. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"84072","DOI":"10.18632\/oncotarget.11432","article-title":"Acquisition cancer stemness, mesenchymal transdifferentiation, and chemoresistance properties by chronic exposure of oral epithelial cells to Arecoline","volume":"7","author":"Wang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1007\/s00432-013-1499-9","article-title":"Expression of E-cadherin, twist, and p53 and their prognostic value in patients with oral squamous cell carcinoma","volume":"139","author":"Fan","year":"2013","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1172\/JCI73941","article-title":"The role for autophagy in cancer","volume":"125","author":"White","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/jop.12593","article-title":"Clathrin-mediated endocytosis is required for ANE 30-100k-induced autophagy","volume":"47","author":"Lin","year":"2017","journal-title":"J. Oral Pathol. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"4054","DOI":"10.7150\/jca.29765","article-title":"Multifaceted mechanisms of areca nuts in oral carcinogenesis: The molecular pathology from precancerous condition to malignant transformation","volume":"10","author":"Li","year":"2019","journal-title":"J. Cancer"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Yen, C.-Y., Chiang, W.-F., Liu, S.-Y., Lin, C.-C., Liao, K.-A., Lin, C.-Y., Hsieh, W.-F., Cheng, Y.-C., Hsu, K.-C., and Lin, P.-Y. (2015). Impacts of autophagy-inducing ingredient of areca nut on tumor cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0128011"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Ji, W.-T., Lee, C.-I., Chen, J.Y.-F., Cheng, Y.-P., Yang, S.-R., Chen, J.-H., and Chen, H.-R. (2013). Areca nut extract induces pyknotic necrosis in serum-starved oral cells via increasing reactive oxygen species and inhibiting gsk3\u03b2: An implication for cytopathic effects in betel quid chewers. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063295"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"725","DOI":"10.4161\/auto.6.6.12423","article-title":"Areca nut extract induced oxidative stress and upregulated hypoxia inducing factor leading to autophagy in oral cancer cells","volume":"6","author":"Lu","year":"2010","journal-title":"Autophagy"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1111\/j.1349-7006.2012.02294.x","article-title":"Arecoline downregulates levels of p21 and p27 through the reactive oxygen species\/mTOR complex 1 pathway and may contribute to oral squamous cell carcinoma","volume":"103","author":"Ji","year":"2012","journal-title":"Cancer Sci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/0165-7992(82)90029-X","article-title":"Chromosome-breaking ability of arecoline, a major betel-nut alkaloid, in mouse bone-marrow cells in vivo","volume":"103","author":"Panigrahi","year":"1982","journal-title":"Mutat. Res. Lett."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/0165-1218(81)90058-6","article-title":"Potentiation of genotoxicity by concurrent application of compounds found in betel quid: Arecoline, eugenol, quercetin, chlorogenic acid and MN2+","volume":"90","author":"Stich","year":"1981","journal-title":"Mutat. Res. Genet. Toxicol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1093\/carcin\/5.4.501","article-title":"Mutagenicity of betel quid and its ingredients using mammalian test systems","volume":"5","author":"Shirname","year":"1984","journal-title":"Carcinogenesis"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1093\/carcin\/21.7.1365","article-title":"Areca nut extract up-regulates prostaglandin production, cyclooxygenase-2 mRNA and protein expression of human oral keratinocytes","volume":"21","author":"Jeng","year":"2000","journal-title":"Carcinogenesis"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1007\/s00784-011-0604-1","article-title":"Arecoline induced cell cycle arrest, apoptosis, and cytotoxicity to human endothelial cells","volume":"16","author":"Tseng","year":"2011","journal-title":"Clin. Oral Investig."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1159\/000092505","article-title":"Protein kinases that regulate chromosome stability and their downstream targets","volume":"1","author":"Nojima","year":"2006","journal-title":"Genome Dis."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.oraloncology.2010.01.003","article-title":"Arecoline arrests cells at prometaphase by deregulating mitotic spindle assembly and spindle assembly checkpoint: Implication for carcinogenesis","volume":"46","author":"Wang","year":"2010","journal-title":"Oral Oncol."},{"key":"ref_125","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_126","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1677\/erc.0.0060045","article-title":"Activation of p53 by oncogenes","volume":"6","author":"Lowe","year":"1999","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1002\/jcb.25074","article-title":"Regulation of hypoxia-inducible factor-1a by reactive oxygen species: New developments in an old debate","volume":"116","author":"Movafagh","year":"2015","journal-title":"J. Cell. Biochem."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"50781","DOI":"10.18632\/oncotarget.9549","article-title":"Current relevance of hypoxia in head and neck cancer","volume":"7","author":"Bredell","year":"2016","journal-title":"Oncotarget"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"311","DOI":"10.3892\/ol.2013.1371","article-title":"Oxygen metabolism in oral cancer: HIF and Gluts (review)","volume":"6","author":"Pereira","year":"2013","journal-title":"Oncol. Lett."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1111\/jop.12513","article-title":"Limited mouth opening in oral submucous fibrosis: Reasons, ramifications, and remedies","volume":"46","author":"Sharma","year":"2016","journal-title":"J. Oral Pathol. Med."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"S276","DOI":"10.1016\/j.semcancer.2015.09.007","article-title":"Designing a broad-spectrum integrative approach for cancer prevention and treatment","volume":"35","author":"Block","year":"2015","journal-title":"Semin. Cancer Biol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1111\/jop.12488","article-title":"The role of hypoxia in oral cancer and potentially malignant disorders: A Review","volume":"46","author":"Kujan","year":"2016","journal-title":"J. Oral Pathol. Med."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/nrm1366","article-title":"Oxygen sensing by HIF hydroxylases","volume":"5","author":"Schofield","year":"2004","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.jfma.2017.02.019","article-title":"Regulation of hypoxia-inducible factor-1\u03b1 in human buccal mucosal fibroblasts stimulated with arecoline","volume":"116","author":"Ho","year":"2017","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1111\/jop.12284","article-title":"Hypoxic regulation of plasminogen activator inhibitor-1 expression in human buccal mucosa fibroblasts stimulated with arecoline","volume":"44","author":"Tsai","year":"2014","journal-title":"J. Oral Pathol. Med."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/jop.12102","article-title":"Long-term stimulation of areca nut components results in increased chemoresistance through elevated autophagic activity","volume":"43","author":"Yen","year":"2013","journal-title":"J. Oral Pathol. Med."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"7729","DOI":"10.18632\/oncotarget.13890","article-title":"Hypoxia induced bcl-2\/TWIST1 complex promotes tumor cell invasion in oral squamous cell carcinoma","volume":"8","author":"Duan","year":"2016","journal-title":"Oncotarget"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.3892\/ol.2013.1549","article-title":"Notch signaling induces EMT in OSCC cell lines in a hypoxic environment","volume":"6","author":"Ishida","year":"2013","journal-title":"Oncol. Lett."},{"key":"ref_140","first-page":"605","article-title":"Hypoxic condition and prognosis in oral squamous cell carcinoma","volume":"34","author":"Jorge","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1186\/s13046-018-0972-3","article-title":"Hypoxia potentiates gemcitabine-induced stemness in pancreatic cancer cells through AKT\/Notch1 signaling","volume":"37","author":"Zhang","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.21873\/anticanres.11419","article-title":"Induced pluripotent-stem-cell related genes contribute to de-differentiation in oral squamous cell carcinoma","volume":"37","author":"Takeda","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_143","first-page":"114","article-title":"The oral microbiota as part of the human microbiota\u2014Links to general health","volume":"130","year":"2020","journal-title":"Nor. Tannlegeforen. Tid."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"153303381986735","DOI":"10.1177\/1533033819867354","article-title":"Role of oral microbiome signatures in diagnosis and prognosis of oral cancer","volume":"18","author":"Chattopadhyay","year":"2019","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Chen, L., Yuan, F., Chen, S., Li, X., Kong, L., and Zhang, W. (2022). Potential role of host microbiome in areca nut-associated carcinogenesis and addiction. Molecules, 27.","DOI":"10.3390\/molecules27238171"},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Rowi\u0144ska, I., Szyperska-\u015alaska, A., Zariczny, P., Pas\u0142awski, R., Kramkowski, K., and Kowalczyk, P. (2021). The influence of diet on oxidative stress and inflammation induced by bacterial biofilms in the human oral cavity. Materials, 14.","DOI":"10.3390\/ma14061444"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"22613","DOI":"10.18632\/oncotarget.4209","article-title":"Periodontal pathogens porphyromonas gingivalis and fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model","volume":"6","author":"Gallimidi","year":"2015","journal-title":"Oncotarget"},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Hernandez, B.Y., Zhu, X., Goodman, M.T., Gatewood, R., Mendiola, P., Quinata, K., and Paulino, Y.C. (2017). Betel nut chewing, oral premalignant lesions, and the oral microbiome. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172196"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1111\/odi.13545","article-title":"Oral microbiota alteration associated with oral cancer and areca chewing","volume":"27","author":"Zhong","year":"2020","journal-title":"Oral Dis."}],"container-title":["Clinics and Practice"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2039-7283\/13\/2\/30\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:37:53Z","timestamp":1760121473000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2039-7283\/13\/2\/30"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,21]]},"references-count":149,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["clinpract13020030"],"URL":"https:\/\/doi.org\/10.3390\/clinpract13020030","relation":{},"ISSN":["2039-7283"],"issn-type":[{"value":"2039-7283","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,21]]}}}