• areca nut and betel quid
• cancer control
• incidence
• mortality
• oral cavity
• oropharynx

• Humans
• Taiwan/epidemiology
• Mouth Neoplasms/epidemiology
• Mouth Neoplasms/mortality
• Mouth Neoplasms/prevention & control
• Mouth Neoplasms/etiology
• Incidence
• Areca/adverse effects
• Male
• Female
• Registries
• Middle Aged
• Adult
• Aged

• HOCl
• animal model
• areca nut
• bleomycin
• oral submucous fibrosis

• Evidence-based dentistry
• Global prevalence
• Oral submucous fibrosis

• Humans
• Oral Submucous Fibrosis/epidemiology
• Prevalence
• Male
• Female
• Risk Factors
• Adult
• Middle Aged

• adult
• humans
• abdominal pain
• antioxidants
• dexamethasone
• drug-related side effects and adverse reactions
• oral submucous fibrosis
• oral submucous fibrosis/therapy
• pentoxifylline
• vasodilator agents

• Adult
• Humans
• Oral Submucous Fibrosis/therapy
• Pentoxifylline
• Drug-Related Side Effects and Adverse Reactions
• Vasodilator Agents
• Abdominal Pain
• Antioxidants
• Dexamethasone

• TGF-β signaling pathway
• areca nut extract
• collagen deposition
• fibrosis
• oral submucous fibrosis
• simvastatin

• chewing tobacco
• oral leukoplakia
• oral mucosal lesions
• oral submucous fibrosis
• potentially malignant lesions
• smoking tobacco

• HDAC8
• Oral submucous fibrosis

• Areca nut
• areca nut chewers
• oral submucous fibrosis
• prevalence
• systematic review

• arecoline
• betel quid
• cessation
• epidemiology
• oral potentially malignant disorders
• oral squamous cell carcinoma

• Areca/adverse effects
• Humans
• Mouth Neoplasms/chemically induced
• Mouth Neoplasms/epidemiology
• Nuts/adverse effects
• Precancerous Conditions/pathology
• Risk Factors

Oral potential malignant disorders (OPMDs) are a precancerous condition of oral disease. Several studies have found that betel quid chewing, smoking and alcohol drinking might be the risk factors of OPMDs. But the relationships of them, especially their interaction are still inconclusive.

To evaluate the relationship between betel quid chewing and OPMDs and to explore the interaction of smoking and alcohol drinking on the relationship.

We searched PubMed, Web of Science, Embase and the Cochrane Library databases with items complete until January 2021 for relevant studies. The research data were extracted according to the inclusion criteria. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the effect size. Subgroup analysis was performed to assess interactions between exposures and OPMDs. Relative excess risk of interaction (RERI) was used to estimate the size of interaction.

Nine articles were selected in the final meta-analysis. The results showed that betel quid chewing (pooled OR: 8.70, 95%CI: 5.18-14.61), alcohol consumption (pooled OR: 1.95, 95%CI: 1.5-2.55), and smoking (pooled OR:4.35, 95%CI: 3.06-6.2) could significantly increase the risk of OPMDs compared to individuals without these behaviors. Smoking and alcohol drinking synergistically increased the association between betel quid chewing and OPMDs (pooled OR_(BQ+SM):14.38, 95%CI: 7.14-28.95; pooled OR_(BQ+DK): 11.12, 95%CI: 8.00-15.45, respectively). The RERI_(BQ+SM) and RERI_(BQ+DK) were 2.33 and 1.47, respectively.

The synergistic effects between smoking/drinking and betel quid highlights the importance of focusing on individuals with multiple exposures. Further study should be conducted to confirm these interactions.

• Oral potential malignant disorders
• Betel quid chewing
• Smoking
• Drinking
• Synergistic effect

Oral submucous fibrosis (OSMF) is a premalignant condition with a greater prevalence in countries such as India. Various classifications have been put forth by multiple authors to determine the clinical, functional, and histopathological grade of the disease. The classification systems have greatly helped to determine the treatment modality for the patients. Understanding the correlation between the various classifications will help us determine the course of the disease, management, and prognosis of OSMF. This study assesses the correlation between clinical, functional, and histopathological grading of OSMF.

To assess the correlation between clinical staging, functional staging, and histopathological grading of OSMF.

Thirty patients with clinical and histopathological diagnosis of OSMF were assigned into clinical stage, functional stage, and histopathological grade. The correlation between these three stages assigned was studied.

The degree of agreement between the clinical, functional, and histopathological classifications was quantified by the Weighted Kappa statistics. Correlation between the three classifications was done using Kendall's tau and Spearman's correlation coefficient.

There was a good agreement and statistically significant correlation between clinical and functional grading. There was a poor agreement and no significant correlation between clinical and histopathological grading. There was a poor agreement and no significant correlation between functional and histopathological grading.

• Clinical staging
• functional staging
• histopathological grading
• oral submucous fibrosis

Areca nut (AN) was identified as carcinogenic to humans. Around 600 million people globally use AN in some form, yet no effective therapeutic drug is available to overcome AN addiction. This preclinical study examines the effects of antidepressants on AN use with animal models. We produced AN powder and dissolved it into drinking water, training 55 C57BL/6 mice in free self-selection to drink AN water or normal water. Then, the mice were randomly divided into four groups. Selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs) were given as three treatment groups and one placebo group for four weeks. In the follow-up period, the preference and amount of free selection of AN and normal water, and oral pathological change were evaluated. There was a significant decrease in preference for AN drinking during the first four weeks, and the 36th week after drug withdrawal in the MAOI and SSRI groups (all p < 0.05). The drug-reducing effect of AN water in the 1–4-week period was significant in the MAOI group (p < 0.0001) and was also significant in the 3–4-week period in the SSRI group (p = 0.03). The TCA group did not show a decrease effect. At the endpoint (60 weeks), oral mucosal fibrosis (OSF) levels and risk in the SSRI (p = 0.0081) and MAOI (p = 0.01) groups were significantly lower than those in the control group. Antidepressant drugs MAOIs and SSRIs could reduce the amount of AN use and decrease the early stage of oral fibrosis in mice, but SSRIs may need to be boosted again.

• antidepressants
• areca nut
• betel quid
• mouse model
• oral cancer
• oral submucous fibrosis

• MicroRNA-21
• Myofibroblast
• Oral submucous fibrosis
• TGF-β pathway

• Areca
• Arecoline/pharmacology
• Cell Transdifferentiation
• Fibroblasts
• Humans
• MicroRNAs/genetics
• Mouth Mucosa
• Oral Submucous Fibrosis/genetics

Arecoline is an alkaloid natural product found in the areca nut that can induce oral submucous fibrosis and subsequent development of cancer. However, numerous studies have shown that arecoline may inhibit fibroblast proliferation and prevent collagen synthesis.

High doses of arecoline (> 32 μg/ml) could inhibit human oral fibroblast proliferation, while low doses of arecoline (< 16 μg/ml) could promote the proliferation of human oral fibroblasts. Wnt5a was found to be both sufficient and necessary for the promotion of fibroblast proliferation. Egr-1 could mediate the expression of Wnt5a in fibroblasts, while NF-κB, FOXO1, Smad2, and Smad3 did not. Treatment with siRNAs specific to Egr-1, Egr inhibitors, or Wnt5a antibody treatment could all inhibit arecoline-induced Wnt5a upregulation and fibroblast proliferation.

Egr-1 mediates the effect of low dose arecoline treatment on human oral mucosa fibroblast proliferation by transactivating the expression of Wnt5a. Therefore, Egr inhibitors and Wnt5a antibodies are potential therapies for treatment of oral submucosal fibrosis and oral cancer.

• Arecoline
• Egr-1
• Fibrosis
• Oral submucous fibroblast
• Wnt5a

Betel-quid (BQ) is a commonly used psychoactive substance that renders a specific cardiotoxicity. The purpose of this study was to investigate the association between BQ chewing and premature ventricular contractions (PVC) in patients with cardiopulmonary symptoms, and examine the potential influences of cardiovascular and chronic diseases on such relationship. Participants were 146 patients with cardiopulmonary symptoms who participated in 24-h Holter electrocardiogram monitoring during 2012–2018 in a hospital serving residents that lived in a BQ high prevalence area. Data on substance uses and medical histories for cardiovascular and chronic diseases were collected. Baron–Kenny method was employed to evaluate possible mediation. In patients with cardiopulmonary symptoms, 36.3% were BQ users and 63.7% were nonusers. Adjusting for covariates, BQ chewing was significantly associated with heart failure and diabetes mellitus (adjusted odds ratio (aOR) = 3.4 and 2.3, respectively), but only heart failure was significantly correlated with a low and high level of PVC. Additionally controlling for the effect of heart failure, the risk of high PVC for BQ users reduced from 3.60 to 2.88; however, the risk for BQ chewers remained significant (95% CI: 1.06–7.84). Heart failure was found to explain 27.7% of the excessive effect of BQ use on high PVC. In conclusion, BQ use is directly associated with an elevated risk of high PVC in patients with cardiopulmonary symptoms. The higher risk might be elevated among patients who suffered heart failure. Given several research limitations, the findings from this study offer future opportunities for validation.

• areca nut
• betel-quid
• cardiovascular disease
• heart failure
• premature ventricular contraction
• substance use

• hyaluronidase
• meta-analysis
• oral submucous fibrosis

• Areca nut
• South Asia
• South East Asia
• betel quid

• Betel quid
• occupation
• oral cancer
• oral potentially malignant disorders
• screening
• smoking

• Areca nut
• betel quid
• chewing tobacco
• intervention
• piper betel
• prevalence
• terminology

• Areca
• Asia, Southeastern/epidemiology
• Bangladesh
• Cambodia
• Humans
• India
• Indonesia
• Malaysia
• Myanmar
• Nuts
• Pakistan
• Taiwan

Identification and comparison of gene expression of Lysyl oxidase (LOX) in oral submucous fibrosis and controls and to determine its role in Pathogenesis of Oral submucous fibrosis.

Of total sample size (n=127), the whole blood sample were collected from case and control group in citrate vial. It is centrifused and stored at -800C. We collected and isolated RNA from blood of case group (n=127) and age and sex matched control group (n=127) recruited on the basis of inclusion criteria. The cDNA was prepared for 127 samples which were processed for gene expression of Lysyl oxidase (LOX) in relation to housekeeping genes (Beta actin and 18srRNA) and its role in pathogenesis of Oral submucous fibrosis.

In relative expression (Normalized ratio),relatively 11 cases shown down-regulation of lysyl oxidase gene while 27 cases shows up-regulation of lysyl oxidase gene while in 89 cases there were no regulation i.e expression of lysyl oxidase gene in case group was of same degree of control. In non-relative expression results (Non-normalized ratio), the 38 cases shown down regulation of LOX gene while in 53 cases, it was up-regulated however in remaining 36 cases there was neither up-regulation nor down-regulation of Lysyl oxidase gene i.e the expression of LOX gene is null.

In oral submucous fibrosis, the expression of Lysyl oxidase gene is mixed type i.e either it will down regulate/upregulate or there will be no expression at all comparatively. However in majority of cases the upregulation of lysyl oxidase is relatively more common than down-regulation or non expression of Lysyl oxidase gene.

Key words:Oral submucous fibrosis, lysyl oxidase, betel nut, premalignant disorders.

Oral submucous fibrosis (OSMF) is a chronic debilitating condition of the oral mucosa that has been classified as a potentially malignant disorder with a malignant transformation rate of 2%–8%. Several in vitro and in vivo experiments have been performed to formulate a treatment modality for OSMF, yet no ideal in vitro primary oral fibroblast model has been developed.

To establish an in vitro primary oral fibroblast model.

In vitro laboratory setting.

Primary cell culture protocol was performed after obtaining normal oral tissue. Karyotyping was performed to rule out chromosomal abnormalities. Immunofluorescence staining was carried with a panel of fibroblast-specific markers (vimentin, phalloidin, transforming growth factor-β receptor 1 [TGFβR1] and s100a4) and Masson trichrome staining (MTS) to demonstrate the presence of extracellular matrix (ECM) qualitatively.

A monolayer of oral fibroblasts was observed on the 9^th-day postseeding. No chromosomal abnormality was observed in the patient samples. Positive staining was observed with vimentin, phalloidin, TGFβR1 and s100a4, thereby confirming the cell type. MTS revealed fibroblasts with spindle morphology and scanty ECM.

The present study lays down a protocol to design and characterize primary buccal fibroblast cell culture model that would aid researchers in performing in vitro preliminary experiments in areas concerning fibrosis.

• Fibrosis
• oral fibroblasts
• phalloidin
• transforming growth factor

• animal model
• arecoline
• mechanical stimulation
• oral submucous fibrosis

• Taiwania cryptomerioides
• Taiwanin C
• anticancer
• cell cycle
• cytotoxicity
• oral cancer

• 4-Nitroquinoline-1-oxide/toxicity
• Animals
• Antineoplastic Agents, Phytogenic/pharmacology
• Apoptosis/drug effects
• Arecoline/toxicity
• Carcinoma, Squamous Cell/chemically induced
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• ErbB Receptors/antagonists & inhibitors
• Humans
• Lactones/pharmacology
• Lignans/pharmacology
• Male
• Mice, Inbred C57BL
• Mouth Neoplasms/chemically induced
• Mouth Neoplasms/metabolism
• Mouth Neoplasms/pathology
• Phosphoinositide-3 Kinase Inhibitors

To examine if periodontitis is independently associated with oral potentially malignant disorders (OPMD) in a rural Indian adult population aged 35-54 years.

A population-based cross-sectional study was conducted in rural India from 2011 to 2012. Multistage stratified cluster random sampling was followed to recruit 1401 participants aged 35-54 years. Face-to-face interviews were conducted to collect data on sociodemographic factors, tobacco and alcohol use. Oral examinations were done to record OPMD, periodontal findings and missing teeth. Univariate, bivariate and multivariable analyses were achieved using SPSS version 16 Chicago, SPSS Inc. OPMDs (leukoplakia, erythroplakia, oral submucous fibrosis (OSF) and suspicious malignant lesion) whether present or absent were selected as outcome variables; age, sex, socioeconomic factors, smoking, tobacco-chewing status, alcohol use, and periodontitis were considered as the predictor variables.

Among 873 participants, 44 demonstrated 47 lesions. Leukoplakia (n=21), erythroplakia (n=3), OSF (n=21), and suspicious malignant lesions (n=2) were present, strongly associated with past tobacco-chewing status [OR=9.22 (2.57-33.15)], current tobacco-chewing status [OR=15.49 (6.20-38.74)] and moderate/severe periodontitis [OR=3.19 (1.11-9.12)].

Periodontitis is a risk indicator for OPMD, independent of socioeconomic factors and tobacco-chewing. Tobacco-chewing status, both past and current, was strongly associated with OPMD in our rural Indian population.

• Oral potentially malignant disorders
• periodontitis
• prevalence
• rural
• socioeconomic position

• Autofluorescence
• Oral potentially malignant disorders
• Sensitivity and specificity

Oral submucous fibrosis (OSF) is a potentially malignant disorder which causes fibrosis and inflammation of the oral mucosa. Studies have reported altered levels of trace elements in oral submucous fibrosis subjects, but findings have been inconsistent. The objective of this research is to perform a meta-analysis to summarize studies that report zinc (Zn), copper (Cu), and iron (Fe) in patients, with and without OSF. A literature search of Embase, PubMed, Cochrane Library, and Web of Science electronic databases was conducted for studies up to January 2017. A total of 34 reports met the inclusion criteria. The standardized mean difference was utilized as the effect size. The robust variance estimation method was chosen to handle dependency of multiple related outcomes in meta-analysis. There was a significant increase in the levels of Cu (effect size = 1.17, p value < 0.05, 95% confidence interval (CI): 0.164–2.171) and a significant decrease in levels of Zn (effect size = −1.95, p value < 0.05, 95% CI: −3.524 to −0.367) and Fe (effect size = −2.77, p value < 0.01, 95% CI: −4.126 to −1.406) in OSF patients. The estimation of Zn, Cu, and Fe levels may serve as additional biomarkers in the diagnosis and prognosis of OSF along with the clinical features.

• Animals
• Carcinogens/toxicity
• Humans
• Mouth/pathology
• Mouth Neoplasms/etiology
• Pharyngeal Neoplasms/etiology
• Piper betle/adverse effects
• Risk Factors

• National Health Insurance
• Taiwan
• nationwide population
• oral submucous fibrosis
• prevalence

Tobacco use can alone lead to death worldwide, especially in developing and underdeveloped countries. China and Brazil are the world's largest producer of tobacco. India holds the third place in producing, and it is the fourth largest consumer of tobacco and its products in the world.

A case–control study was carried out to assess the influence of risk factors on patients with potentially malignant disorders (PMD) and oral cancer.

Fifty cases diagnosed with PMD and oral cancer patients were selected for the study. An equal number 50 healthy controls who were also selected after age and gender matching. Multivariate logistic regression analysis was used to estimate the suspected risk factors for PMD and oral cancers. Chi-square test, Adjusted odd's ratios with 95% confidence interval were also used for the statistical analysis.

There is a statistically significant difference between the different age group, duration, frequency, exposure time, and synergistic effect of tobacco chewing, smoking and alcohol drinking.

Chewing tobacco is one of the major risk factors in the initiation of PMD which can lead to oral cancer.

• Oral cancer
• potentially malignant disorders
• tobacco/betel quid

• Odds ratio
• Oral precancer
• Pan masala
• Potentially malignant disorder
• Prevalence

Dental informatics is an evolving branch widely used in dental education and practice. Numerous applications that support clinical care, education and research have been developed. However, very few such applications are developed and utilized in the epidemiological studies of oral submucous fibrosis (OSF) which is affecting a significant population of Asian countries.

To design and develop an user friendly software for the descriptive epidemiological study of OSF.

With the help of a software engineer a computer program SOFPRO was designed and developed by using, Ms-Visual Basic 6.0 (VB), Ms-Access 2000, Crystal Report 7.0 and Ms-Paint in operating system XP. For the analysis purpose the available OSF data from the departmental precancer registry was fed into the SOFPRO.

Known data, not known and null data are successfully accepted in data entry and represented in data analysis of OSF. Smooth working of SOFPRO and its correct data flow was tested against real-time data of OSF.

SOFPRO was found to be a user friendly automated tool for easy data collection, retrieval, management and analysis of OSF patients.

• Dental informatics
• SOFPRO software
• descriptive epidemiology
• oral submucous fibrosis

• betel quid chewing
• de novo malignancy
• head and neck malignancy
• liver transplantation

• Adult
• Aged
• Areca/adverse effects
• Female
• Humans
• Incidence
• Liver Transplantation
• Male
• Middle Aged
• Neoplasms/epidemiology
• Neoplasms/etiology
• Postoperative Complications/epidemiology
• Postoperative Complications/etiology
• Retrospective Studies
• Risk Factors
• Taiwan/epidemiology

• betel nut
• betel quid
• fibrosis
• oral disease
• squamous cell carcinoma
• tobacco

• Copper
• Home drinking water
• Oral submucous fibrosis
• Pathogenesis

Oral submucous fibrosis (OSF) is considered as a pre-cancerous condition of the oral mucosa and is highly associated with habitual areca quid chewing. Arecoline is the major alkaloid in areca quid and is thought to be involved in the pathogenesis of OSF. Our previous studies have demonstrated that arecoline could induce epithelial–mesenchymal transition (EMT)-related factors in primary human buccal mucosal fibroblasts (BMFs). Therefore, we investigated the expression of zinc finger E-box binding homeobox 1 (ZEB1), which is a well-known transcriptional factor in EMT, in OSF tissues and its role in arecoline-induced myofibroblast transdifferentiation from BMFs. The expression of ZEB1, as well as the myofibroblast marker α-smooth muscle actin (α-SMA), was significantly increased in OSF tissues, respectively. With immunofluorescence analysis, arecoline induced the formation of α-SMA-positive stress fibres in BMFs expressing nuclear ZEB1. Arecoline also induced collagen contraction of BMFs in vitro. By chromatin immunoprecipitation, the binding of ZEB1 to the α-SMA promoter in BMFs was increased by arecoline. The promoter activity of α-SMA in BMFs was also induced by arecoline, while knockdown of ZEB1 abolished arecoline-induced α-SMA promoter activity and collagen contraction of BMFs. Long-term exposure of BMFs to arecoline induced the expression of fibrogenic genes and ZEB1. Silencing of ZEB1 in fibrotic BMFs from an OSF patient also suppressed the expression of α-SMA and myofibroblast activity. Inhibition of insulin-like growth factor receptor-1 could suppress arecoline-induced ZEB1 activation in BMFs. Our data suggest that ZEB1 may participate in the pathogenesis of areca quid–associated OSF by activating the α-SMA promoter and inducing myofibroblast transdifferentiation from BMFs.

• ZEB1
• arecoline
• buccal mucosal fibroblasts
• myofibroblasts
• oral submucous fibrosis
• α-SMA

• Adult
• Age Distribution
• Aged
• Areca/adverse effects
• Case-Control Studies
• Female
• Humans
• Malaysia/epidemiology
• Male
• Middle Aged
• Mouth Neoplasms/epidemiology
• Mouth Neoplasms/etiology
• Mouth Neoplasms/pathology
• Prevalence
• Reference Values
• Risk Assessment
• Sex Distribution
• Smoking/adverse effects
• Survival Analysis
• Tobacco, Smokeless/adverse effects
• Young Adult

In the 20th century, 100 million people across the globe lost their lives due to consumption of tobacco. Every year 15,000 deaths in Nepal are attributable to tobacco smoking and using other products of tobacco. This study aimed to establish the proportion and the social determinants of tobacco use among Nepalese men based on the Nepal Demographic and Health Survey (NDHS), 2011.

This study used the NDHS 2011 data. The prevalence of cigarette smoking, other forms of tobacco 16 smoking and use of tobacco in any form is reported as a percentage (%). The significance of association of the statistically significant variables established using Chi-square test was further tested by using multiple logistic regression.

Of the 4121 participants, the prevalence of consuming any form of tobacco was 51.9% [95% confidence interval (CI) (49.6%- 54.3%)]; chewing/sniffing tobacco was 34.8% (95% CI: 32.4%- 37.3%) and tobacco smoking was 33.6% (95% CI 31.3%-36.0%).

Men with no education [Odds Ratio (OR) 3.477; 95% CI (2.380-5.080)], from an older age group (36–49) [OR 2.399; 95% CI (1.858-3.096)] who were from a manual occupation [OR 1.538; 95% CI (1.188-1.985)], who were married[OR 1.938; 95% CI ( 1.552-2.420)], and who were from the Terai region [OR 1.351; 95% CI (1.083-1.684)] were more likely to consume tobacco. Men who watched television at least once a week [OR 0.642; 95% CI (0.504-0.819)] were less likely to consume tobacco.

The current study showed that over half of Nepalese men consume tobacco. There is an urgent need to fully implement Nepal’s Tobacco Control and Regulation Act which will ban smoking in public places; enforced plain packaging and display of health warnings over 75% of the packaging, and has banned selling of tobacco products to those under 18 years of age. There is a need to increase the social unacceptability of tobacco in Nepal by raising awareness through different electronic and cultural media. Anti-tobacco campaigns should focus on those who are less educated, have manual occupations, are in poorer economic groups, and are from the Terai region of Nepal.

• Areca nut
• Gutkha chewers
• Moradabad
• Oral submucous fibrosis