• Environment
• Epigenomics
• Immune system
• Microbiota
• Mutation
• Oral squamous cell carcinoma
• Precancerous conditions
• Risk factors

• Humans
• Precancerous Conditions/pathology
• Mouth Neoplasms/pathology
• Mouth Neoplasms/etiology
• Cell Transformation, Neoplastic/pathology
• Carcinoma, Squamous Cell/pathology
• Risk Factors
• Disease Progression

• Humans
• Oral Submucous Fibrosis/genetics
• Mouth Neoplasms/genetics
• Carcinoma, Squamous Cell/genetics
• Gene Expression Profiling
• Protein Interaction Maps
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks

• MIAT
• SOX6
• long non-coding RNA
• miR-342-3p
• oral submucous fibrosis

• MicroRNAs/genetics
• MicroRNAs/metabolism
• Oral Submucous Fibrosis/genetics
• Oral Submucous Fibrosis/metabolism
• Oral Submucous Fibrosis/pathology
• Humans
• Myofibroblasts/metabolism
• Myofibroblasts/pathology
• SOXD Transcription Factors/genetics
• SOXD Transcription Factors/metabolism
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Mouth Mucosa/pathology
• Mouth Mucosa/metabolism
• Areca/adverse effects
• Apoptosis/genetics
• Arecoline/pharmacology

• FSCN1
• MetaLnc9
• Oral submucous fibrosis
• miR-143

• malignant transformation
• oral cancers
• oral malignancy
• oral sub mucous fibrosis
• trace elements

• active components
• areca nut
• clinical study
• influencing factors
• omics
• pharmacology
• quality detection

• Major Science and Technology Project of Hainan Province
• Natural Science Foundation of Hainan Province

• oral submucous fibrosis (osmf/osf)
• oxidant damage and antioxidants
• vitamin a deficiency
• vitamin c deficiency
• vitamin e deficiency

• FAP
• areca nut extract
• fibroblasts
• fibrosis
• oral submucous fibrosis

• Humans
• Oral Submucous Fibrosis/metabolism
• Oral Submucous Fibrosis/pathology
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Areca
• Serine Endopeptidases/metabolism
• Serine Endopeptidases/genetics
• Fibroblasts/drug effects
• Fibroblasts/metabolism
• Membrane Proteins/metabolism
• Membrane Proteins/genetics
• Male
• Endopeptidases/metabolism
• Female
• Adult
• Arecoline/pharmacology
• Signal Transduction
• Alkaloids/pharmacology
• Plant Extracts/pharmacology
• Middle Aged

• 82170972 National Natural Science Foundation of China
• 82201081 National Natural Science Foundation of China

• 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

• Ascorbic acid
• iron
• oral submucous fibrosis
• saliva
• serum

• Buccal fat pad
• Nasolabial flap
• OSMF
• Superficial flap

• Areca nut
• Edible methods
• Edible parts
• Feature-based molecular networking
• Ingredients comparison
• UPLC-Q-TOF-MSE

• alkaloids
• areca nut
• benzenoids
• betel quid
• metabolomics
• terpenes

• Humans
• Areca/chemistry
• Indonesia
• Safrole
• Alkaloids/chemistry
• Terpenes
• Aldehydes

Areca nut, used alone or in combination with tobacco, contributes to the high oral cancer burden in India. Used widely by adolescents, who perceive it as a harmless substance, areca nut is addictive and considered a precursor to tobacco use. Given its serious implications for addictiveness and physical health, urgent preventive interventions for areca nut use are required in India and South-East Asia. Studies examining the role of health behavior theory in explaining and predicting areca nut use and for development of its prevention among adolescents are scarce.

This study explored the role of the components of Theory of Planned Behavior (TPB) such as attitudes, subjective norms, perceived behavioral control, and intention in predicting areca nut use among adolescents.

Observational study with cross-sectional design conducted with 1884 male and female adolescents attending low-income schools in Mumbai, India.

Self-administered surveys were used to gather data on age, gender, behavioral factors and areca nut use.

Chi-square and Mann Whitney test for bivariate and logistic regression for multivariate analysis.

Around 27.2% of 1884 participants were areca nut users. The mean age of users was 13.75 years. Intention-to-use and perceived behavioral control were statistically significant predictors of actual areca nut use (p<0.001). The components of TPB such as attitude, perceived subjective social norms, and perceived behavioral control had a statistically significant effect on the intention-to-use areca nut (p<0.05).

This exploratory study indicates that constructs from TPB could help us understand and predict areca nut use. However, more rigorous future research is required to generate insights that help craft effective theory-based behavioral interventions for areca nut prevention and cessation in adolescents.

• India
• adolescents
• areca nut
• supari
• theory of planned behavior

Oral submucous fibrosis (OSF) is a chronic progressive condition affecting the oral cavity, oropharynx and upper third of the oesophagus. It is a potentially malignant disorder. The authors collated and analysed the existing literature to establish the overall malignant transformation rate (MTR). A retrospective analysis of medical and dental scientific literature using online indexed databases was conducted for the period 1956 to 2021. The quality of the enrolled studies was assessed by the Newcastle-Ottawa Scale (NOS). A meta-analysis using a random effects model of a single proportion was performed along with statistical tests for heterogeneity. The overall proportion of malignancy across all studies was 0.06 (95% CI, 0.02–0.10), indicating an overall 6% risk of malignant transformation across all studies and cohorts. Sub-group analyses revealed strong differences in proportion of malignancy according to ethnicity/cohort; Chinese = 0.02 (95% CI 0.01–0.02), Taiwanese = 0.06 (95% CI, 0.03–0.10), Indian = 0.08 (95% CI, 0.03–0.14) and Pakistani = 0.27 (95% CI 0.25–0.29). Overall, the MTR was 6%; however, wide heterogeneity of the included studies was noted. Geographic variations in MTR were noted but were not statistically significant. Further studies are required to analyse the difference between cohort groups.

• areca nut
• betel nut
• malignant transformation rate
• oral cancer
• oral potentially malignant disorders
• oral squamous cell carcinoma
• oral submucous fibrosis

• Humans
• Oral Health
• Oral Submucous Fibrosis/drug therapy
• Oral Submucous Fibrosis/psychology
• Quality of Life/psychology
• Surveys and Questionnaires

Many studies have shown that most genomes are transcribed into non-coding RNAs (ncRNAs), including microRNAs (miRs) and long non-coding RNAs (lncRNAs), which can affect different cell characteristics. LncRNAs are long heterologous RNAs that regulate gene expression and various signaling pathways during homeostasis and development. Studies have shown that a lncRNA is an important regulatory molecule that can be targeted to change the physiology and function of cells. Expression or dysfunction of lncRNAs is closely related to various genetic, autoimmune, and metabolic diseases. The importance of ncRNAs in oral submucosal fibrosis (OSF) has garnered much attention in recent years. However, most research has focused on miRs. The role of these molecules in OSF is incompletely understood. This review focuses on the emerging role and function of lncRNAs in OSF as novel regulators. Finally, the potential functional role of lncRNAs as biomarkers for OSF diagnosis is also described. LncRNAs are expected to become a new therapeutic target, but more research is needed to understand their biological functions more deeply.

• biomarker
• function
• long non-coding RNAs
• mechanism
• oral submucous fibrosis

• molecular alterations
• morphological features
• oral potentially malignant disorders
• risk factors and etiology
• treatment

• OSF
• disease pathogenesis
• immune
• inflammation
• pathology

• Vascular endothelial growth factor (VEGF)
• angiogenesis
• gene transfection
• oral submucous fibrosis (OSF)

The diagnostic role and correlation between phosphatase and tensin homologue and alpha-smooth muscle actin in oral submucous fibrosis and oral squamous cell carcinoma with concomitant oral submucous fibrosis was analysed by this case control study. The mechanism by which phosphatase and tensin homologue controls myofibroblast expression was also evaluated.

Overall, 10 normal mucosa, 30 oral submucous fibrosis (OSF) and 30 oral squamous cell carcinoma (OSCC) with OSF were stained immunohistochemically with phosphatase and tensin homologue (PTEN) and alpha-smooth muscle actin (α-SMA). Percentage positivity, pattern of expression was statistically compared using Pearson’s Chi-square and Fischer exact tests. The correlation between markers was analysed using Spearman correlation.

OSF and OSCC affected males predominantly with majority below 40 years and above 40 years of age respectively. Percentage of PTEN positive cells was statistically significant with gender (P = 0.024) and α-SMA distribution of pattern showed a significant correlation with habits (P = 0.018). A significant decrease in nuclear PTEN positivity (P < 0.001) and a gradual increase in α-SMA cytoplasmic expression was noted from NM to OSF and OSCC. A statistically significant weak inverse correlation existed between PTEN and α-SMA.

A reduced phosphatase and tensin homologue expression in oral submucous fibrosis makes it more prone for malignant transformation. An increase in stromal desmoplasia modifies differentiation, invasive and proliferative capacity of tumour cells. As phosphatase and tensin homologue functions through P-Akt pathway, P-Akt with phosphatase and tensin homologue could be a therapeutic target.

• immunohistochemistry
• myofibroblast
• oral cancer
• oral submucous fibrosis
• prognosis
• tumor suppressor gene

• ApoTome
• E-cadherin
• mitotic figures
• oral submucous fibrosis
• p63

• Biopsy
• Cadherins
• Cell Transformation, Neoplastic
• Humans
• Mouth Neoplasms
• Oral Submucous Fibrosis

Betel quid (BQ) is a chewing mixed package that mainly contains areca nut (AN), betel leaf (Leaf) or betel stem inflorescence (SI), and slaked lime, and is consumed with or without tobacco BQ chewing is common in South East Asia and has been strongly associated with malignant and potentially malignant diseases of the oral cavity. Alkaloids such as arecoline are often accounted for the carcinogenic potential of BQ, however the chemical composition of BQ has not been studied in detail. In the current study, we investigated the total phenolic content (TPC), antioxidant activity (by mean of ferric reducing antioxidant power, FRAP), radical scavenging activity (DPPH test), polyphenolic profile and arecoline content in different components of BQ, namely AN, Leaf or SI, Husk, and blended BQ (BQ mix, containing AN, Leaf or SI and slaked lime). Samples were imported from 4 major regions of Indonesia, namely: Banda Aceh (BA), North Sumatra (NS), West Kalimantan (WK) and West Papua (WP). The highest TPC, FRAP, and DPPH values were detected in AN samples compared to other BQ components, while samples from WP region were of higher values compared to the other regions. High performance liquid chromatography—Mass Spectrometry (LC–MS) analysis showed that Husk contains the widest range of polyphenols, including hydroxybenzoic acids, hydroxycinnamic acids, flavanols, flavonols and stilbenes. Catechin and epicatechin were the main polyphenols detected in BQ, and they were present at the highest concentrations in WP–AN sample. Arecoline was detected in all AN and BQ mix samples and was significantly correlated with catechin and epicatechin, and significantly negatively correlated with p-hydroxybenzoic acid. Notably, arecoline concentration changed significantly when AN was blended in BQ mixtures. The current study is the first to extensively characterise the chemical composition of BQ and provides insight for a better understanding of the interactions of BQ alkaloids and phenolics in the development of oral submucous fibrosis and oral cancer.

• Oral submucous fibrosis
• Polymerase chain reaction
• TGF-β
• TGF-β isoforms
• TGF-β receptors
• Transforming growth factor beta

• Alkaloids
• Areca Nut (AN)
• Arecoline
• Cancer
• Metabolism
• Pharmacology
• Toxicity

• Alkaloids/pharmacokinetics
• Alkaloids/pharmacology
• Alkaloids/toxicity
• Animals
• Areca/chemistry
• Carcinogens/pharmacokinetics
• Carcinogens/pharmacology
• Carcinogens/toxicity
• Dose-Response Relationship, Drug
• Humans
• Neoplasms/chemically induced
• Neoplasms/metabolism
• Nuts/chemistry

• antioxidants
• curcumin
• oral potentially malignant disorder
• oral submucous fibrosis
• turmeric

Oral submucous fibrosis (OSF) is characterized by abnormal collagen deposition. It is a precancerous disorder and transforms into a malignant tumor in 1.5–15% of all cases. Symptoms include submucous fibrosis, ulceration, xerostomia, a burning sensation, and restricted mouth opening. All of these greatly interfere with patient quality of life. The present review introduces OSF from a molecular perspective and summarizes what is known about its underlying mechanisms, diagnostic biomarkers, and therapeutic interventions. In addition to the aggressive treatment of OSF, its prevention is also important. Future research should, therefore, focus on improving the oral health literacy of the patients susceptible to OSF.

• collagen deposition
• diagnostic biomarkers
• oral submucous fibrosis (OSF)
• precancerous disorder
• therapeutic interventions
• underlying mechanisms

• areca nut
• associated lesions
• clinicopathological features
• oral submucosa fibrosis

• Adult
• Areca
• China/epidemiology
• Female
• Humans
• Leukoplakia, Oral/epidemiology
• Leukoplakia, Oral/pathology
• Male
• Middle Aged
• Mouth Mucosa/pathology
• Oral Submucous Fibrosis/epidemiology
• Oral Submucous Fibrosis/pathology

• 2018dcyj062 graduate investigation research project of Central South University
• 2017GK2265 China Hunan Provincial Science and Technology Program

This study was aimed to evaluate the collagen fibers qualitatively and its correlation with microvascular density in various grades of oral submucous fibrosis (OSMF).

The present study comprised of total 40 cases of oral submucous fibrosis. Picrosirius red staining was done on all the specimens’ sections. They were analyzed for the colour and orientation of collagen fibers. Morphometric measurements were done using image analysis on immunohistochemical stained sections for Factor VIII-related antigen and analyzed for microvascular density.

Picrosirius red polarizing microscopy results revealed that there was a shift in the colour of collagen fibers from greenish yellow to orange red and red colour as the severity of the oral submucous fibrosis increased. The collagen fibers showed mixed orientation in early oral submucous fibrosis and parallel orientation in advanced oral submucous fibrosis. There was a significant decrease in microvascular density from early to advanced oral submucous fibrosis.

The change in the colours and orientation of collagen fibers in early and advanced oral submucous fibrosis could be attributed to the fibre thickness, type of collagen, alignment and packing, cross-linking of the fibers and the section thickness. However, in advanced cases the vascularity is reduced which may predispose to epithelial atrophy and subsequent malignant changes.

• Immunohistochemistry
• Morphometry
• Muscle Fibers
• Oral Submucous Fibrosis
• Picrosirus red

To compare self-perceived oral symptoms and clinical (plaque index [PI], bleeding on probing [BOP], clinical attachment loss [CAL]) and radiographic (marginal bone loss [MBL]) periodontal parameters among naswar (NW) and non-naswar dippers (NNW).

One hundred and forty-two individuals (72 patients consuming naswar and 70 controls) were included. All participants completed a baseline questionnaire that included information regarding demographic characteristics and self-perceived oral symptoms. Clinical periodontal parameters (PI, BOP, PD and CAL) were recorded. MBL was measured on digital panoramic radiographs.

Pain in teeth, pain on chewing, bleeding gums and burning sensation in the mouth was significantly worse among NW than NNW (p<0.01). Clinical periodontal parameters and MBL were significantly high in NW than NNW (p<0.001). There was statistically significant influence of daily use and mean duration of naswar consumption on the severity of PI, BOP, PD (4 to 6 and >6 mm) and MBL among NW group.

Self-perceived oral symptoms and periodontal parameters were worse among naswar dippers. It is highly recommended that naswar dipping should be considered a potential threat that could have major effects on periodontal tissues.

• Alveolar bone loss
• Inflammation
• Periodontitis
• oral symptoms New tobacco products

• Diode laser
• Fibrotomy
• Habit correlation
• Oral submucous fibrosis

Oral submucous fibrosis (OSMF) is a chronic debilitating disease of the oral cavity having premalignant potential and unclear pathogenesis. Recently, myofibroblast has been postulated to play an important role in its pathogenesis and in the process of carcinogenesis. The purpose of this study was to evaluate and compare the presence of myofibroblasts in normal mucosa, different grades of OSMF, and oral squamous cell carcinoma (OSCC).

The present in vitro cross-sectional descriptive study sample consisted of three groups, including 40 OSCCs, 40 OSMF, and 10 sections of normal oral epithelium taken as control group. Alpha-smooth muscle actin was used to identify myofibroblasts using immunohistochemical technique. P < 0.05 was taken as statistically significant.

The presence of myofibroblasts was significantly higher in OSMF cases when compared with normal epithelium specimens. The presence of myofibroblasts was significantly higher in OSCC compared to OSMF cases. A significant difference was not observed between the different grades of OSCC.

These findings favor the possibility that OSMF actually represents an abnormal healing process in response irritation caused by areca nut. A significant increase in myofibroblasts in OSCC as compared to OSMF also highlights the possible role it may play in the malignant transformation of OSMF.

• Alpha-smooth muscle actin
• myofibroblast
• oral squamous cell carcinoma
• oral submucous fibrosis

• malignant transformation
• oral submucous fibrosis
• review
• squamous cell carcinoma

• Hainan
• dried betel nut
• fresh betel nut
• oral cancer
• oral mucosal disease

• areca nut
• oral submucous fibrosis
• squamous cell carcinoma
• tobacco

• Ferrozine method
• Iron
• Precancerous conditions
• Sahli’s Method
• Trace element

Oral submucous fibrosis (OSF) is an oral potentially malignant disorder and areca quid chewing is the main etiological factor. However, the molecular mechanism underlying OSF remains unclear, partly due to the lack of an appropriate animal model. The present study aimed to establish and characterize an animal model of areca nut extract (ANE)-induced skin fibrosis that mimics OSF. Mice were divided into 4 groups: the control group; the bleomycin group; and the ANE10 and ANE20 groups, which received 10mg/ml and 20mg/ml subcutaneous (SC) injection of ANE, respectively. Skin fibrosis was evaluated by histological analyses. Additionally, the expression levels of the fibrotic marker genes were determined by immunohistochemical staining and immunoblotting. ANE administration significantly increased dermal thickness and collagen deposition compared with the control group. Moreover, ANE induced the expression of the fibrotic marker genes alpha smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF) in the skin lesions. The SC injection of ANE successfully induced skin fibrosis, exhibiting characteristics similar to those of OSF. This model may facilitate future studies of the mechanism underlying OSF.

• Animals
• Areca/adverse effects
• Collagen/metabolism
• Dermis/pathology
• Disease Models, Animal
• Injections, Subcutaneous
• Intercellular Signaling Peptides and Proteins/metabolism
• Male
• Mice, Inbred BALB C
• Nuts/adverse effects
• Oral Submucous Fibrosis/genetics
• Oral Submucous Fibrosis/pathology
• Plant Extracts/adverse effects

• Ministry of Science and Technology, Taiwan
• Kaohsiung Medical University Aim for the Top Universities Grants

• Breath Alkane
• Diagnosis
• Oral submucous fibrosis
• Oxidative stress

Oral submucous fibrosis (OSF) is potentially premalignant with progressive and irreversible extracellular matrix deposition accompanied by epithelial atrophy and like other fibrotic disorders, is primarily a TGF-β driven disease. OSF is caused by prolonged chewing of areca nut. Our previous studies reported a pivotal role for TGF-β activation and its effects contributing to OSF. However, the mechanism for activation of TGF-β signaling in OSF is still unknown. In this study we demonstrate activation of TGF-β signaling with sub-cytotoxic dose of areca nut in epithelial cells and discovered a key role for pJNK in this process. In good correlation; pJNK was detected in OSF tissues but not in normal tissues. Moreover, activation of JNK was found to be dependent on muscarinic acid receptor induced Ca²⁺/CAMKII as well as ROS. JNK dependent phosphorylation of ATF2/c-Jun transcription factors resulted in TGF-β transcription and its signaling. pATF2/p-c-Jun were enriched on TGF-β promoter and co-localized in nuclei of epithelial cells upon areca nut treatment. In corroboration, OSF tissue sections also had nuclear pATF2 and p-c-Jun. Our results provide comprehensive mechanistic details of TGF-β signaling induced by etiological agent areca nut in the manifestation of fibrosis which can lead to new therapeutic modalities for OSF.

The aim of this study was to quantitatively investigate the hypermethylation of p16 gene in buccal cells and saliva of oral submucous fibrosis (OSMF) patients using real-time quantitative methylation-specific polymerase chain reaction (PCR) and to compare the values of two methods.

A total of 120 samples were taken from 60 subjects selected for this study, of which 30 were controls and 30 patients were clinically and histopathologically diagnosed with OSMF. In both groups, two sets of samples were collected, one directly from the buccal cells through cytobrush technique and the other through salivary rinse. We analyzed the samples for the presence of p16 hypermethylation using quantitative real-time PCR.

In OSMF, the hypermethylation status of p16 in buccal cells was very high (93.3%) and in salivary samples, it was partially methylated (50%). However, no hypermethylation was found in controls suggesting that significant quantity of p16 hypermethylation was present in buccal cells and saliva in OSMF.

This study indicates that buccal cell sampling may be a better method for evaluation than the salivary samples. It signifies that hypermethylation of p16 is an important factor to be considered in epigenetic alterations of normal cells to oral precancer, i.e. OSMF.

• CpG islands
• epigenetic
• hypermethylation
• oral submucous fibrosis
• p16