Association between habitual betel quid chewing and risk of adverse cardiovascular outcomes: A systematic review.

INTRODUCTION: Habitual betel quid chewing, a tobacco product, is a leading cause of oral cancer in Asia-Pacific countries where this practice is most prevalent. However, it is not well understood whether betel quid chewing is also a cause of adverse cardiovascular outcomes. To address this gap, we conducted a systematic literature review of peer-reviewed published studies evaluating the association between habitual betel quid use on the risk of adverse cardiovascular outcomes. METHODS: We searched PubMed for studies assessing the correlation between betel quid chewing and cardiovascular health. We included studies if (i) they included human subjects; (ii) were peer-reviewed articles in indexed journals; and (iii) were in English. We extracted data from eligible studies and stratified them by geographical location, study designs and cardiovascular outcomes. Finally, we did a narrative synthesis of the data to identify adverse cardiovascular outcomes associated with chronic betel quid use. FINDINGS: We reviewed data from 19 studies that met the inclusion criteria. Habitual betel quid chewing was associated with hypertension, atherosclerosis, inflammation and ischaemic heart disease. In addition, betel quid use was a risk factor for arrhythmias. Interestingly, betel quid use was an independent risk factor for cardiovascular disease in women. Long-term betel quid consumption was associated with higher risks for all-cause mortality and increased overall cardiovascular risk. CONCLUSIONS: Habitual betel quid chewing is an important cardiovascular risk factor in populations where the practice is prevalent.

Communication and Social Determinants of Cancer Preventive Behaviors in Adolescents From Low Socio-Economic Backgrounds in India: A Cross-Sectional Study.

PURPOSE: Promoting cancer preventive behaviors among adolescents, especially those from lower socioeconomic backgrounds, is crucial due to the significant impact of health behaviors in adolescence on disease risk in adulthood. With India witnessing a rise in cancer incidence and mortality, adolescence becomes a pivotal stage for establishing healthy habits, emphasizing the need for early cancer prevention efforts. METHODS: This cross-sectional study used survey data from 2242 adolescents attending public schools of Mumbai, India. Multiple logistic regression was conducted to determine the associations between cancer preventive behaviors and: (1) the individual and social determinants of health, and (2) media exposure. FINDINGS: Merely 21.5% of the adolescents ate fruits and vegetables daily, 50% of the adolescents exercised 3 or more times a week, and 20% of the adolescents admitted having used tobacco and/or supari. Girls were found to have lower odds of exercising, as well as using tobacco and/or supari. Wealth and father's education were positively associated with all 3 cancer preventive behaviors. Media exposure was negatively associated, with television exposure linked to reduced fruits and vegetables consumption, while movies and social media exposure were associated with increased tobacco and/or supari use. INTERPRETATION: Our findings suggest that individual and social determinants of health and media exposure can influence cancer preventive health behaviors in low socio-economic status (SES) adolescents. Efforts to increase awareness to promote cancer preventive behaviors among the adolescents, particularly low SES adolescents, a population more vulnerable to poor health outcomes, is critical.

This study investigates factors that can influence cancer preventive behaviors among low socioeconomic status (SES) adolescents, focusing on dietary habits, physical activity, and avoidance of tobacco and areca nut. Our study gathered data from an underrepresented population of India, which is more vulnerable to poor health outcomes and have less access to health care. Our findings can alert public health officials, policy makers and non-governmental organizations to target this population and customize their intervention strategies to promote health and prevent cancer.

Serum and salivary Cu/Zn ratio as a diagnostic biomarker for oral submucosal fibrosis: an analysis of trace metals and LOX gene variants.

This study aimed to analyze the serum and salivary levels of copper (Cu), zinc (Zn), iron (Fe), chromium (Cr), manganese (Mn) and the Cu/Zn ratio and investigate the association between LOX gene variants (rs18800449 and rs2288393) and oral submucosal fibrosis (OSMF). A total of 250 subjects were included in the study: OSMF patients (n = 50), areca nut chewers without OSMF (n = 100) and controls (n = 100). Trace metals were measured using an atomic absorption spectrophotometer, while LOX gene variants were genotyped using the tetra primer amplification refractory mutation system (tetra ARMS) polymerase chain reaction (PCR) method. The results showed significant variations in serum and salivary Cu, Zn, Fe and Cr levels and serum Mn concentrations among the three groups (p < 0.0001). Serum Cu levels were significantly higher in OSMF patients, while serum Zn levels were significantly lower. Both serum and salivary Cu/Zn ratios demonstrated a statistically significant difference (p < 0.0001) and diagnostic potential to differentiate OSMF from chewers and controls. However, LOX gene variants did not show an association between OSMF and chewers, except for rs1800449 genotypes, which showed a significant and increased risk with the AA genotype in OSMF patients compared to controls (OR = 7.58; 95%CI 2.30-24.97). The study suggests that trace elements and genetic variants may impact the etiology of OSMF. The findings may aid in early diagnosis, suitable treatment, and as a prognostic indicator for disease progression.

Areca nut-induced AREG promote oral epithelial cell proliferation, migration, and EMT.

OBJECTIVE: To analyze the biological effect and mechanism of areca nut extract (ANE) on human oral keratinocyte (HOK) cells. MATERIALS AND METHODS: The effect of gradient concentration of ANE on the proliferation activity of HOK cells was analyzed by cell counting kit-8 (CCK-8) assays. The differentially expressed genes between the ANE group and control group HOK cells were analyzed by second-generation transcriptome sequencing. Real-time PCR and western blot were, respectively, used to analyze the expression of AREG gene and protein in HOK cells. After AREG gene overexpression or knockdown, the proliferation, migration, and expression of proteins related to epithelial-mesenchymal transformation (EMT), MAPK signal pathway in HOK cells were, respectively, detected by CCK-8, wound healing, transwell, and western blot assays. RESULTS: ANE (500 µg/mL) promoted the proliferation and migration of HOK cells, ANE (2 mg/mL) promoted the EMT of HOK cells, and ANE (50 mg/mL) inhibited the proliferation of HOK cells. AREG knockdown inhibited ANE-induced proliferation and migration of HOK cells, while AREG overexpression promoted the proliferation and migration of HOK cells. Western blot assay showed that ANE activated MAPK signal pathway by upregulating AREG protein in HOK cells. CONCLUSIONS: ANE promoted HOK cell proliferation, migration, and EMT by mediating AREG-MAPK signaling pathway.

Areca nut and oral cancer.

INTRODUCTION: The association between areca nut consumption and oral cancer has been a subject of increasing concern in global public health. GLOBAL PERSPECTIVE: Areca nut, often chewed in various forms such as betel quid, is deeply rooted in cultural practices across Asia and other parts of the world. Epidemiological studies consistently reveal a significant correlation between areca nut use and the incidence of oral cancer, emphasizing the need for targeted preventive measures. The complex interplay of areca nut's bioactive compounds, particularly arecoline, with cellular processes, contributes to the initiation and progression of oral carcinogenesis. Mechanistic insights into the genotoxic and cytotoxic effects of its components underscore the urgency for comprehensive public health interventions. PUBLIC HEALTH: Efforts to address this public health challenge involve multidisciplinary approaches, encompassing education, policy implementation, and behavioral interventions. Understanding the socio-cultural factors influencing areca nut consumption is pivotal for designing effective awareness campaigns and cessation programs. CONCLUSION: As oral cancer remains a significant global health burden, unraveling the nuanced relationship between areca nut and its role in oral carcinogenesis is crucial for advancing preventive strategies and mitigating the impact of this modifiable risk factor.

Current advances of oral cancer in Taiwan.

OBJECTIVES: To provide updated statistics of oral cancer incidence and mortality in Taiwan, and to describe recent developments for oral cancer control to reduce oral cancer incidence and mortality. METHODS: The Taiwan Cancer Registry Annual Report 2023, the Taiwan Cancer Registry Online Interactive Search System, and the 2023 Health Promotion Administration Annual Report are consulted and summarized. A literature search using PubMed was also conducted to identify Taiwan oral cancer control-related studies. RESULTS: Taiwan, with a long history of areca/betel quid chewing, has battled with oral cancer for decades. In 2021, the male lip and oral cavity cancer incidence is 29.77 (per 100,000 persons) and mortality is 11.25. Over these years, the male chewing prevalence was reduced to 6.2% in 2018. Taiwan has a sustained national oral cancer screening programme provided to high-risk groups biennially. CONCLUSIONS: Although the age-standardized incidence rates have been slowly decreasing since 2009, due to Taiwan's ageing population, the actual oral cancer burden is still stringent. The collaboration of multi-ministries and agencies on promoting areca nut and betel quid control, improving oral cancer awareness, and delivering cancer care remains essential to prevent oral cancer and reduce oral cancer deaths.

What Motivates Betel Quid Chewers to Quit? An Analysis of Several Cessation-Relevant Variables.

Introduction: Betel quid (BQ) is globally the fourth most consumed psychoactive substance. It is consumed by an estimated 600 million people worldwide, accounting for nearly 8% of the world's population. There have been very few studies assessing chewers' motivation to quit. Objectives: In the current study, we sought to understand the relationship between several cessation-relevant variables and chewers' motivation to quit. Hypotheses: Based on analogous research on cigarette smoking, we hypothesized that the following cessation-relevant variables would be associated with motivation to quit: health risk perceptions, number of chews per day, cost, degree of BQ dependence, withdrawal symptoms, number of quit attempts, reasons for use, personal health improvement, and type of BQ chewed. Methods: A total of 351 adult BQ chewers from Guam participated in the survey and served as the sample for the analyses. Results: Majority of chewers want to quit and intend to quit. Chewers relatively high in motivation to quit evinced greater health risk perceptions of BQ chewing, greater perceived health benefits to quitting, and a greater number of past quit attempts, compared to those relatively low in motivation to quit. Conclusions: Understanding which factors are associated with chewers' motivation to quit can be helpful for designing BQ cessation programs. The results suggest that BQ cessation programs could be improved by an increased emphasis on information about the negative health effects of BQ chewing and relapse-prevention.

Ameliorative Effect of Areca Nut Polyphenols on Adverse Effects Induced by Lipopolysaccharides in RAW264.7 Cells.

In Asian regions, areca nuts are tropical fruits that are extensively consumed. The areca nut contains a lot of polyphenols and its safety is unknown. In this research, we investigated the effects of lipopolysaccharides (LPS) and areca nut polyphenols (ANP) on normal RAW264.7 cells. The results showed that LPS stimulated adverse effects in normal cells by affecting cytokine production. The GO analysis results mainly affected DNA repair, cell division, and enzyme activities. In the KEGG analysis results, the NOD-like receptor signaling pathway, which is related to NF-κB, MAPK, and the pro-inflammatory cytokines, is the most significant. In the protein-protein interaction network (PPI) results, significant sub-networks in all three groups were shown to be related to cytokine-cytokine receptor interaction. Collectively, our findings showed a comprehensive understanding of LPS-induced toxicity and the protective effects of ANP by RNA sequencing.

Simvastatin Attenuates Areca Nut Extract-Induced Subdermal Fibrosis in Mice by Targeting TGF-ß Signaling Pathways.

Oral submucous fibrosis (OSMF) is a chronic inflammatory disease and a potentially malignant oral disorder, characterized by fibrosis of the oral mucosa. TGF-ß signaling pathways have been implicated in the development of OSMF, with areca nut extract (ANE) contributing to the disease progression. Simvastatin, a statin drug, has demonstrated anti-fibrotic properties in various fibrotic conditions. However, its therapeutic potential in treating OSMF remains unclear. In this study, 8-week-old male BALB/c mice were randomly divided into three groups based on different time points. Each mouse was then treated with four different drug formulations. Post-treatment, specimens were collected for histopathological examination and staining to assess skin thickness, fibrosis, and collagen deposition. ANE treatment alone significantly increased skin thickness and collagen deposition compared to the control group after the 4-week time point. The combined administration of ANE and simvastatin, resulted in a notable reduction in skin thickness and collagen deposition. Western blot analysis revealed that simvastatin effectively suppressed the expression of fibrosis-related proteins, including CTGF, and α-SMA, in ANE-induced subdermal fibrosis. These results suggest that simvastatin has potential therapeutic effects on ANE-induced subdermal fibrosis, providing a foundation for future studies and possible clinical applications.

Cost effective porous areca nut carbon nanospheres for adsorptive removal of dyes and their binary mixtures.

Novel porous nanospheres from areca nuts (ACNPs) were synthesized via one-step pyrolysis without the use of any chemical treatment and the materials were used as adsorbents for the removal of cationic methylene blue (MB) and anionic methyl orange (MO) as well as their binary mixtures. Around, 6-7 tonnes of areca nut biowaste is generated every year which are then burnt due to their slow rate of decomposition resulting in higher carbon footprints. Biosorbents are generally a preferable alternative for dye adsorption but involve chemical modification for surface enhancement and complex sample treatment. In this work, ACNPs, were investigated for their efficiency in the raw form and were characterized by SEM, EDS, FTIR, XRD, and BET techniques before and after subjecting to the dye adsorption studies. The BET analysis of the adsorbents showed a high specific surface area of 693.8 m2/g when prepared at 1000 °C, while the N2 adsorption-desorption plot showed type-IV isotherm, suggesting the microporous nature of the carbon matrix. Batch equilibrium studies showed the removal efficiency of >95% for both the dyes and their binary mixtures under the optimum conditions of 0.15 g/L dosage, 10 µM concentration and contact time of 70 min. Due to the synergistic effects of the binary dyes, higher removal efficiency of MB compared to MO was observed in the binary mixture. Adsorption results were tested using Langmuir, Freundlich, Temkin, Redlich-Peterson, and Elovich isotherms to assess the best fit of the models. The qm value of MB was found to be 97.37 mg/g, while that of MO was 71.22 mg/g which is higher compared to individual dye components having lower values of 86.12 mg/g and 50.35 mg/g, respectively. Extended Langmuir and Jain and Snoeyink isotherms were used for binary data interpretation. The kinetic results showed good agreement with the Pseudo-second order equation, indicating internal diffusion. The possible mechanism involved electrostatic and á´¨-á´¨ interactions between the dye molecules and ACNPs. This approach is comprehensible and cost effective and can be utilized for dye removal in textile industries.

Integrated metabolomics and network pharmacology to reveal the mechanism of areca nut addiction.

As a chewing hobby, areca nut (Areca catechu L.) has become the most common psychoactive substance in the world, besides tobacco, alcohol and caffeinated beverages. Moreover, as a first-class carcinogen designated by International Agency for Research on Cancer, long-term chewing areca nut can result in oral mucosal diseases and even oral cancer. To clarify the potential mechanism of areca nut addiction, an integrated strategy of metabolomics and network pharmacology was adopted in this study. Network pharmacology study indicated that all the key targets related to areca nut addiction could be regulated by arecoline and pointed out the importance of G-protein coupled receptor signalling pathway. Analysis results of mice plasma metabolome and faeces metabolome intervened by arecoline suggested that the component may affect the dopamine system and 5-HT system by regulating phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, primary bile acid biosynthesis, glycerophospholipid metabolism and intestinal flora structure. Moreover, the potential importance of bile acids in formation of addictive behaviour of chewing areca nut was investigated by integrative analysis of the relationships between metabolites and intestinal flora. The study can provide scientific basis for the addiction intervention and treatment of areca nut chewers.

Prevalence of oral submucous fibrosis among areca nut chewers: A systematic review and meta-analysis.

BACKGROUND: Worldwide millions peoples consume AN who are at risk of OSMF. Prevalence of OSMF is reported between 0.03% and 30% irrespective of AN habit. Further, these estimates are based on sample population comprised of OSMF patients or general population rather AN chewers (ANC). Therefore, available evidence does not reflect the true prevalence of OSMF among ANC. METHOD: The studies providing the prevalence of OSMF in ANC were identified in PubMed, Scopus, and Web of Science. Pooled prevalence and quality assessment using New-Ottawa Scale were performed. RESULTS: Fifteen studies reported the prevalence of OSMF (929) in ANC (53,213). Most studies were from China (six studies) and India (four studies) correlating with regions having high ANC. The pooled prevalence of OSMF in ANC was 5% (0.05 [95% CI, 0.03, 0.08]). All studies' quality was satisfactory; however, the OSMF diagnosis method, age, gender, and habits need further scrutiny. CONCLUSION: Available evidence suggested a low prevalence of OSMF in ANC, although further large-scale studies are recommended to validate this finding. Understanding the prevalence and distribution patterns of OSMF might aid intervention healthcare programs and contribute to the reduction of the oral cancer burden related to OSMF.

Fibroblast activating protein promotes the proliferation, migration, and activation of fibroblasts in oral submucous fibrosis.

OBJECTIVES: Fibroblast activating protein (FAP) is associated with various organ fibrosis. However, the expression and molecular function of FAP in oral submucous fibrosis (OSF) is still unclear. MATERIALS AND METHODS: The high-performance liquid chromatography was used to detect the presence of alkaloids in areca nut extract (ANE). Real-time qPCR, Western blot, and Immunohistochemistry assay were used to analyze the expression of FAP mRNA or protein in OSF and normal oral tissue. A chi-squared test analyzed the relationship between FAP protein expression and clinicopathological data of OSF patients. CCK-8, Wound-healing, and Transwell migration assay were employed to assess the effect of the proliferation and migration ability of hOMF cells with FAP overexpression or knockdown. The expression level of a-SMA, FSP1, and P13K-Akt signaling pathways-related protein in hOMF cells transfected with FAP overexpression or knockdown plasmid was verified by western blot assay. RESULTS: The four specific areca alkaloids (Arecoline, Guvacine, Arecaidine, and Guvacoline) were successfully detected in the ANE. The viability of hOMF cells was significantly improved in the 50 µg/mL ANE group and was inhibited in the 5 and 50 mg/mL ANE groups. The expression of FAP was upregulated in OSF tissues, and hOMF cells treated with 50 µg/mL ANE and was related to pathology grade, clinical stage, and history of chewing betel nut. Additionally, FAP may promote the proliferation, migration, and activation of hOMF cells through the P13K-Akt signaling pathway. CONCLUSIONS: This study found that ANE had a bidirectional effect on the viability of hOMF cells, and the FAP gene was a potential therapeutic target in OSF.

Systematic review of determinants and interventions of areca nut cessation: curbing a public health menace.

BACKGROUND: Areca nut (AN) is a proven human carcinogen and a global public health menace. There is yet no review providing comprehensive information on the determinants and interventions available for cessation of AN. This systematic review was aimed at summarizing the available literature on drivers and interventions for cessation of AN chewing habit and to highlight the research lacunae. METHODS: A systematic literature search (from 1990 till March 2021) was conducted for studies on AN cessation. Relevant data were extracted independently by two authors. RESULTS: A total of 16 studies were included, which highlighted the influence of socio-cultural factors, addictive nature of AN and withdrawal symptoms as barriers to quitting. However, the knowledge of ill-effects of AN use on health, absence of concurrent alcohol use or smoking and family pressure were associated with likelihood of AN cessation. The interventions utilized for AN cessation have been behavioural in majority of the studies except for one where antidepressants were used for this purpose. CONCLUSIONS: The current review emphasizes the imperative need of appropriate cessation strategies for AN chewing habit including enhancing awareness of the harmful effects and research into additional behavioural and pharmacologic cessation therapies to control this significant public health problem.

Comparative metabolomics study on areca nut from China and Southeast Asia (Thailand and Indonesia).

INTRODUCTION: Areca nut is an economic crop and an important component in traditional Chinese medicine (TCM) and ethnomedicine. The crop is rich in alkaloids and flavonoids. Most previous studies have focused on the chemical components, especially alkaloids, in crops from certain areca nut-producing areas. OBJECTIVE: The purpose of this study was to compare the differences in areca nut seeds in two main cultivation areas, identify differential metabolites, and evaluate seed quality in different production areas. METHODS: A widely targeted metabolomics method based on ultrahigh-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QQQ-MS), combined with the TCM systems pharmacology (TCMSP) database and multivariate statistical analysis, was used in this study to maximise the differentiation between quality characteristics of areca nut seeds from China and Southeast Asian regions. RESULTS: Altogether, 1031 metabolites were identified in areca nut seeds; by querying the TCMSP database, 375 metabolites were identified as the main active ingredients. Moreover, the research showed that the metabolic profiles of areca nut seeds from China (ASCN) and Southeast Asia (ASSA) exhibit significant differences, and the difference is mainly reflected in 318 compounds. The relative content of 146 metabolites in ASCN was significantly higher than that in ASSA. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) comparative analysis, areca nut seed metabolites in Chinese production areas were determined to have a wider metabolic pathway. CONCLUSION: The areca nut seeds from cultivation areas possess many metabolites that are beneficial for health, including alkaloids, amino acids, phenolic acids, and lipids. Thus, compared with ASSA, ASCN have a higher medicinal value. This study provides a direction for the subsequent development and utilisation of areca nut seeds.

The Controversial Roles of Areca Nut: Medicine or Toxin?

Areca nut (AN) is used for traditional herbal medicine and social activities in several countries. It was used as early as about A.D. 25-220 as a remedy. Traditionally, AN was applied for several medicinal functions. However, it was also reported to have toxicological effects. In this review article, we updated recent trends of research in addition to acquire new knowledge about AN. First, the history of AN usage from ancient years was described. Then, the chemical components of AN and their biological functions was compared; arecoline is an especially important compound in AN. AN extract has different effects caused by different components. Thus, the dual effects of AN with pharmacological and toxicological effects were summarized. Finally, we described perspectives, trends and challenges of AN. It will provide the insight of removing or modifying the toxic compounds of AN extractions for enhancing their pharmacological activity to treat several diseases in future applications.

Metabolism of the areca alkaloids - toxic and psychoactive constituents of the areca (betel) nut.

Areca nut (AN) is consumed by millions of people for its therapeutic and psychoactive effects, making it one of the most widely self-administered psychoactive substances in the world. Even so, AN use/abuse is associated with myriad oral and systemic side effects, affecting most organ systems in the body. Alkaloids abundant in the nut (e.g. arecoline, arecaidine, guvacoline, and guvacine), collectively called the areca alkaloids, are presumably responsible for the major pharmacological effects experienced by users, with arecoline being the most abundant alkaloid with notable toxicological properties. However, the mechanisms of arecoline and other areca alkaloid elimination in humans remain poorly documented. Therefore, the purpose of this review is to provide an in-depth review of areca alkaloid pharmacokinetics (PK) in biological systems, and discuss mechanisms of metabolism by presenting information found in the literature. Also, the toxicological relevance of the known and purported metabolic steps will be reviewed. In brief, several areca alkaloids contain a labile methyl ester group and are susceptible to hydrolysis, although the human esterase responsible remains presumptive. Other notable mechanisms include N-oxidation, glutathionylation, nitrosamine conversion, and carbon-carbon double-bond reduction. These metabolic conversions result in toxic and sometimes less-toxic derivatives. Arecoline and arecaidine undergo extensive metabolism while far less is known about guvacine and guvacoline. Metabolism information may help predict drug interactions with human pharmaceuticals with overlapping elimination pathways. Altogether, this review provides a first-of-its-kind comprehensive analysis of AN alkaloid metabolism, adds perspective on new mechanisms of metabolism, and highlights the need for future metabolism work in the field.

Quantitative determination of major alkaloids in areca nut products by high-performance liquid chromatography coupled with ion mobility spectrometry.

Areca nut is a popular and addictive food as well as a traditional herbal medicine in many countries. Areca nut contains alkaloids including arecoline, guvacine, and arecaidine, which are the major bioactive compounds in areca products. Areca alkaloids can be carcinogenic, and thus sensitive and specific analytical methods are urgently desired for the identification and quantification of these compounds. High-performance liquid chromatography-based methods are often preferred, but areca alkaloids do not have chromophores, and detection using a traditional UV detector can be difficult. The complexity of areca sample extracts can also lead to the co-elution of peaks leading to poor quantitative performance. We report here high-performance liquid chromatography coupled with an ion mobility spectrometer for sensitive determination of areca alkaloids in various products including areca nut, areca nut products, and herbal oral liquid. An X-Bridge reversed-phase C18 column was used in the experiment and was combined with high-performance liquid chromatography coupled to an ion mobility spectrometer system. A custom-made adjustable post-column splitter acted as an interface between the high-performance liquid chromatography and the ion mobility spectrometer; it also acted as the electrospray ionization source. The mobile phase was methanol and 0.5% ammonium hydroxide. The results demonstrate that the splitter can afford a wide range of split ratios that match the ion mobility spectrometer ionization source while keeping the separation efficiency of high-performance liquid chromatography. Three major alkaloid compounds were then accurately determined using the resulting method without dativization steps. Many coeluted high-performance liquid chromatography peaks are effectively separated in the ion mobility spectrometer dimension, which in turn improved the quantification accuracy.

Betel quid: New insights into an ancient addiction.

The use of areca nuts (areca) in the form of betel quids constitutes the fourth most common addiction in the world, associated with high risk for oral disease and cancer. Areca is a complex natural product, making it difficult to identify specific components associated with the addictive and carcinogenic properties. It is commonly believed that the muscarinic agonist arecoline is at the core of the addiction. However, muscarinic receptor activation is not generally believed to support drug-taking behaviour. Subjective accounts of areca use include descriptions of both sedative and stimulatory effects, consistent with the presence of multiple psychoactive agents. We have previously reported partial agonism of α4-containing nicotinic acetylcholine receptors by arecoline and subsequent inhibition of those receptors by whole areca broth. In the present study, we report the inhibition of nicotinic acetylcholine receptors and other types of neurotransmitter receptors with compounds of high molecular weight in areca and the ability of low molecular weight areca extract to activate GABA and glutamate receptors. We confirm the presence of a high concentration of GABA and glutamate in areca. Additionally, data also indicate the presence of a dopamine and serotonin transporter blocking activity in areca that could account for the reported stimulant and antidepressant activity. Our data suggest that toxic elements of high molecular weight may contribute to the oral health liability of betel quid use, while two distinct low molecular weight components may provide elements of reward, and the nicotinic activity of arecoline contributes to the physical dependence of addiction.

Genome-wide DNA methylation changes in oral submucous fibrosis.

OBJECTIVE: Oral submucous fibrosis (OSF) is a debilitating potentially malignant condition of the buccal cavity characterized by extensive extracellular matrix deposition resulting in stiffness and trismus. As OSF is a progressive disease, we hypothesized that there would be extensive epigenetic changes in OSF tissues. MATERIALS AND METHODS: Using the Infinium HumanMethylation450 BeadChip Array, we analyzed gross DNA methylation changes in seven OSF tissues compared to five controls. Comparison with transcriptomic data and pathway analyses was conducted to find commonly regulated genes. RESULTS: A total of 3,294 differentially methylated regions mapping to 857 genes were identified. Comparison with transcriptome data revealed 38 downregulated-hypermethylated genes and 55 hypomethylated-upregulated genes. Using methylation-specific and qRT-PCR, aberrant hypomethylation and increased expression of FGF13, RPS6KA3, and ACSL4 genes were confirmed. Pathways involved in insulin signaling, ubiquitin-mediated proteolysis, nicotine addiction, and RAS/MAPK pathways were dysregulated, among others. Intriguingly, numerous genes located on the X chromosome were dysregulated in OSF tissues as the transcript for XIST gene was downregulated due to hypermethylation of the XIST promoter. CONCLUSIONS: This study highlights global epigenetic dysregulation of tissues of the oral cavity in OSF patients and hints at possible X chromosomal dysregulation, previously not implicated in the pathogenesis of OSF.